Advances in immunomodulatory microneedles for diabetic wound healing

Abstract

The dysregulated immune microenvironment of diabetic wounds, characterized by aberrant immune cell infiltration, persistent cytokine production, accumulation of metabolic by-products, and elevated oxidative stress, presents substantial clinical challenges to effective wound healing. Microneedles, through the formation of reversible microchannels that enable efficient transdermal drug delivery, offer a promising strategy for immunomodulation and tissue repair. This review comprehensively summarizes recent advances in immunomodulatory microneedles for diabetic wound healing. We discuss key designs and engineering parameters, focusing on how material composition and structural tuning influence immune responses. Special attention is paid to diverse therapeutic modalities delivered via microneedles, including small molecules, proteins, nucleic acids, cells, exosomes, inorganic agents, gaseous therapeutics, and integrated multifunctional platforms. Finally, we outline the current challenges in optimizing microneedle-based immunotherapies and discuss future directions toward clinical translation.

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Shenqiang Wang

Shenqiang Wang, PhD, is a Professor at the College of Pharmaceutical Sciences, Soochow University. He received his doctoral degree from Northwestern Polytechnical University under the supervision of Professor Qiuyu Zhang, followed by postdoctoral training in Professor Zhen Gu's laboratory at the College of Pharmaceutical Sciences, Zhejiang University. In 2023, Dr Wang joined Soochow University, where he leads an interdisciplinary research team focused on the development of controlled drug delivery systems for wound healing and immunotherapy.

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1. Introduction

Diabetes, a chronic metabolic disease characterized by persistent hyperglycemia, affected approximately 537 million adults worldwide in 2021, with projections indicating a rise to 783 million by 2045.¹ As the body's largest organ and primary barrier against external insults, the skin is particularly susceptible to diabetes-related complications. Merely minor injuries would eventually progress into chronic, non-healing wounds—most notably diabetic foot ulcers (DFUs)—which represent one of the most debilitating and prevalent complications of diabetes mellitus, often associated with a heightened risk of infection, amputation and mortality.² The high incidence of diabetic wounds, driven by complex pathophysiology and increased tissue vulnerability, not only complicates treatment but also imposes substantial economic and health burdens on patients and healthcare systems globally.³ Consequently, timely and effective intervention in the progression of diabetic wounds is critical to improving the healing outcomes of diabetic patients.

Cutaneous wound healing is a highly coordinated and dynamic process that comprises four overlapping stages: hemostasis, inflammation, proliferation, and remodeling.⁴ In contrast to acute wounds, which progress through these stages in a timely manner, diabetic wounds often fail to heal within 12 weeks or do not heal at all, due to prolonged stagnation in the inflammatory phase.⁵ Persistent hyperglycemia induces a cascade of cellular and molecular alterations that underlie sustained and excessive inflammation. Moreover, the hyperglycemic microenvironment promotes bacterial proliferation and impairs immune regulation, leading to bacterial colonization and biofilm formation, which further exacerbates chronic inflammation.^6,7 Impaired angiogenesis due to dysfunction of endothelial cells and downregulation of key transcription factors results in insufficient supply of oxygen (O₂) and nutrients essential for wound repair.^8,9 Peripheral neuropathy, a prevalent diabetic complication linked to dysregulated neurotrophic factors and compromised neurovascular supply, stimulates immune cell infiltration and the release of inflammatory factors, thereby sustaining inflammation at the wound site.^10,11 Consequently, therapeutic strategies aimed at modulating and resolving chronic inflammation represent a critical avenue for improving outcomes in diabetic wound management.¹²

Current clinical approaches for managing diabetic wounds primarily include glycemic control, surgical debridement, negative pressure wound therapy, vascularized flap reconstruction, topical antibiotics, and wound dressing application.¹³ While these conventional treatments may partially relieve symptoms, they largely require supportive care at the macroscopic level and fail to address the underlying immunopathological dysfunction at the diabetic wound site. Moreover, commonly used dressings, such as gauze, metal ion-infused materials, hydrogels, electrospun fibers, and platelet-rich plasma formulations, are frequently limited by inadequate drug-loading capacity and suboptimal permeability, impairing their ability to deliver therapeutics effectively to the deep wound bed.¹⁴ Therefore, the development of advanced therapeutic strategies that enable efficient drug delivery and precise modulation of the local immunosuppressive microenvironment is critical for diabetic wound care.

Microneedles (MNs) have emerged as a promising transdermal delivery platform, offering minimal invasiveness, reduced systemic side effects, high drug-loading capacity, robust mechanical strength, ease of application, and improved patient compliance. By penetrating tissue barriers and bacterial biofilms, MNs enable efficient drug delivery and sustained release.¹⁵ Notably, MNs can be engineered to stably incorporate diverse bioactive compounds, enabling multifunctional and synergistic treatment across various phases of wound healing while amplifying immunoregulatory effects. Furthermore, immunomodulatory MNs can dynamically regulate the local immune microenvironment at diabetic wound sites through the targeted and prolonged release of anti-inflammatory agents, contributing to the restoration of immune homeostasis. Therefore, the development of immunomodulatory MNs is a promising strategy for promoting the effective healing of diabetic ulcers.

To date, few reviews have systematically reviewed the advancements in immunomodulatory MNs for the treatment of diabetic wounds. This review aims to provide a comprehensive framework for the design of immunomodulatory microneedle (MN) therapies and to serve as a valuable reference for both research and clinical practice. This review begins by outlining the mechanisms and pathological features of the dysregulated immune microenvironment in diabetic wounds. It then delves into the engineering parameters of immunoregulatory MNs, including material selection and structural design. Subsequently, this review explores the delivery of various therapeutic substances, such as small molecules, proteins, nucleic acids, cells, exosomes, inorganic materials, and gases, via MNs for immune regulation, along with the synergistic strategies that integrate MNs with electrotherapy, phototherapy, and thermotherapy. Finally, this review discusses current challenges in the development of immunomodulatory MNs and proposes potential solutions, offering new insights into future directions and clinical translation (Fig. 1 and Table 1).

Fig. 1 Schematic representation of immunomodulatory MNs for the treatment of diabetic wounds. NETs, neutrophil extracellular traps; M1, M1 macrophages; TNF-α, tumor necrosis factor-alpha; IL-1β, interleukin-1beta; AGEs, advanced glycation end products; MMPs, matrix metalloproteinases; ROS, reactive oxygen species; γ-PGA, poly (γ-glutamic acid); GAGs, glycosaminoglycans; GOx, glucose oxidase; CAT, catalase; IL-4, interleukin-4; bFGF, basic fibroblast growth factor; miRNA, microRNA; siRNA, small interfering RNA; mRNA, messenger RNA; MSCs, mesenchymal stem cells; KCs, keratinocytes; and FBs, fibroblasts.

Table 1 Microneedles for immune regulation in diabetic wound healing

Active ingredients	Type	Materials	Delivered substances	Immune regulation	Functions	Ref.
γ-PGA – poly(γ-glutamic acid), MXene – transition metal carbide/nitride, GOx – glucose oxidase, SDA – dopamine-functionalized sericin protein, HA-FPBA – 4-amino-3-fluorophenylboronic acid functionalized hyaluronic acid, OKGM – oxidized konjac glucomannan, HA – hyaluronic acid, GA – gallic acid, Cu^2+ – copper ions, StarPEG – 4-arm PEG-NH2, PLGA – poly(lactic-co-glycolic acid), PVA – polyvinyl alcohol, SF – silk fibroin, CS – chitosan, EGCG – epigallocatechin gallate, PVP – polyvinyl pyrrolidone, CMC – Na sodium carboxymethyl cellulose, GelMA – gelatin methacrylate, DA – dopamine, LBP – lycium barbarum polysaccharide, SerMA – sericin methacryloyl, PDA – polydopamine, Ag^+ – silver ions, Se-CQDs – selenium-doped carbon quantum dots, HA-ADH – hyaluronic acid modified with hydrazide groups, HA-QA-ALD – hyaluronic acid modified with quaternary ammonium groups and aldehyde groups, KD – kinsenoside, PCL – polycaprolactone, PAM – polyacrylamide, CaO2-HA NPs–sodium hyaluronate-modified CaO2 nanoparticles, TCH – tetracycline hydrochloride, DFO – deferoxamine, Gel-CMC – gelatin-carboxymethyl chitosan, rh-EGF – recombinant human epidermal growth factor, SA-g-PNIPAM – sodium alginate (SA)-g-poly(N-isopropylacrylamide), SOS – sucrose octasulfate sodium salt, AlgMA – sodium methacrylate-alginate, TSA – trichostatin A, PEG – polyethylene glycol, dBRD9 – BRD9 degrader, SAG – hedgehog signaling agonist, HA-β-CD – hyaluronic acid-β-cyclodextrin, HAMA – hyaluronic acid methacrylate, MG – glucose oxidase-loaded 2D MXene nanosheets, MOXNPs – moxifloxacin-loaded chitosan/fucoidan nanoparticles, LH – lidocaine, TH – thrombin, NPF NPs–Nisin@Protocatechualdehyde@Fe nanoparticles, Hb-RES NPs–hemoglobin-resveratrol nanoparticles, ANW – Au nanowire, ε-PLL – epsilon-poly-l-lysine, CGA – chlorogenic acid, Sr^2+ – strontium ions, TA – tannic acid, RES MC – resveratrol micelles, GEN – gentamicin, SOS – sucrose octasulfate, Quer-NCs – quercetin nanocrystals, PDGF-BB – platelet-derived growth factor-BB, PC – purpurolide C, LA – lipoic acid, RY – RADA16-YIGSR peptide, CMCS – carboxymethyl chitosan, BSP – white peony polysaccharide, APB@Ber – astragalus membranaceus polysaccharide nanoparticles, Nap@PLGA – naproxen loaded poly (lactic-co-glycolic acid) nanoparticle, rhCol III recombinant humanized collagen type III, Res@PtZ-Z – resveratrol-loaded ZIF shell encapsulating a Pt-doped ZnO nanozyme core, AFPBA – 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid, G-Insulin – gluconic insulin, PVAMA–methacrylated poly(vinyl alcohol), PBA phenylboronic acid, QDL quaternized chitosan cografted with dihydrocaffeic acid and L-arginine, OHD – oxidized hyaluronic acid-dopamine, POGa – gallium porphyrin modified with 3-amino-1,2 propanediol, PU polyurethane, NIPAM – N-isopropylacrylamide, hEGF – human epidermal growth factor, SA sodium alginate, bFGF – basic fibroblast growth factor, GO-ASyycF – graphene oxide-antisense yycF, IL-4 – interleukin-4, 1-RHC – type 1 recombinant human collagen, PRP – platelet-rich plasma, BS – bromeliad substrate, Alg – alginate, CAT – catalase, QHREDGS – QHREDGS peptide, SilMA – silk fibroin methacryloyl, miRNA-mDTC NPs–miRNA-147-loaded D-mannose/dopamine-enhanced tripolyphosphate-quaternized chitosan nanoparticles, Mn-DCaO2 – NPs manganese/dopamine-enhanced calcium peroxide nanoparticles, Ag-NPs – silver nanoparticles, Co^2+ – cobalt ions, ADSCs – adipose-derived stem cells, GelMA-CS – methacrylate gelatin-chitosan, KCs – keratinocytes, FBs – dermal fibroblasts, H-EVs extracellular vesicles from hair follicle stem cells, MSC-exos – mesenchyal stem cell-derived exosomes, UC-EVs – umbilical cord mesenchymal stem cell vesicles, Fe-MSC-NVs – ferrum-mesenchymal stem cell-derived artificial nanovesicles, PDA NPs  – polydopamine nanoparticles, MEs – M2 macrophage-derived exosomes, PFP – polyvinyl alcohol/2-formylphenylboronic acid/polyetherimide, M2-EVs – M2 macrophage-derived extracellular vesicles, ADMMA-GEL – methacrylated acellular dermal matrix-based hydrogel, PLT-Exos – platelet-derived exosomes, PNS – panax notoginseng saponins, Vn – vancomycin, SeC@PA – dopamine-coated hybrid nanoparticles containing selenium and chlorin e6, SeNPs@LAS – micelle-protected selenium nanoparticles, PEGDA – poly(ethylene glycol) diacrylate, PANI – polyaniline, CIP – ciprofloxacin hydrochloride, GMA-HA – glycidyl methacrylate-hyaluronate, CV – carvacrol, VEGF – vascular endothelial growth factor, Lys-AFs – lysozyme amyloid fibrils, CBAA – carboxybetaine acrylamide, CexMny MMON – cerium–manganese mixed metal oxide nanocomposite, Res@ZIF67 – resveratrol-loaded ZIF-67, PBNs – prussian blue nanozymes, MnO2 – manganese dioxide, H2 –  hydrogen, HEMA – hydroxyethyl methacrylate, HMPP – 2-Hydroxy-2-methyl-1-phenyl-1-propanone, H2S – hydrogen sulfide, PMB – polymyxin B, CO – carbon monoxide, NO – nitric oxide, GelTAMA – gelatin-tannic acid-maleic anhydride, PIL – poly(ionic liquid).
Materials	Dissolvable MNs	γ-PGA, MXene	GOx	Promotes the polarization of macrophages from M1 to M2 and reduces the expression levels of TNF-α, IL-1β, and IL-6	Antibacterial, hypoglycemic, antioxidant, anti-inflammatory, promoting cell proliferation, angiogenesis and collagen deposition	55
	Dissolvable MNs	SDA, HA-FPBA	Verteporfin	Reduces the expression levels of TNF-α and IL-6 and increases the expression levels of IL-4, IL-10 and TGF-β	Ameliorating hypoxia, antioxidant, anti-inflammatory, promoting angiogenesis, collagen deposition and re-epithelialization	57
	Dissolvable MNs	OKGM, HA	GA, Cu^2+	Promotes the polarization of macrophages from M1 to M2	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis, collagen deposition and re-epithelialization	60
	Porous MNs	Heparin, StarPEG, PLGA	—	Reduces the MCP-1 level and decreases monocyte infiltration	Anti-inflammatory, promoting angiogenesis and collagen deposition	62
	Core–shell MNs, dissolvable MNs	Heparin, PVA	verteporfin	Promotes the polarization of macrophages from M1 to M2 and reduces the expression levels of IFN-γ, MCP-1, TNF-α, IL-1β, and IL-6	Antibacterial, anti-inflammatory, promoting angiogenesis, collagen deposition and re-epithelialization	63
Small molecules	Hydrogel MNs	SF, CS fiber	EGCG	EGCG promotes the polarization of macrophages from M1 to M2 and decreases the expression of IL-6	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis, re-epithelialization and collagen deposition	83
	Dissolvable MNs	PVP, CMC–Na	EGCG, Cu^2+	Promotes the polarization of macrophages from M1 to M2 and reduces the expression levels of IL-6	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis, re-epithelialization and collagen deposition	92
	Hydrogel MNs	GelMA	DA, LBP	Promotes the polarization of macrophages from M1 to M2 and reduces the expression levels of TNF-α and IL-6	Antioxidant, anti-inflammatory, promoting neurogenesis	214
	Hydrogel MNs	SerMA	PDA, Ag^+	Reduces inflammatory cell infiltration and the IL-6 level	Antibacterial, anti-inflammatory, promoting collagen deposition	222
	Core–shell MNs, hydrogel MNs	GelMA	Astilbin, Se-CQDs	Promotes the polarization of macrophages from M1 to M2	Antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	102
	Hydrogel MNs	HA-ADH, HA-QA-ALD	KD	Promotes the polarization of macrophages from M1 to M2, reduces the expression levels of TNF-α and MCP-1, and increases the expression levels of IL-10 and TGF-β	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis, re-epithelialization and collagen deposition	223
	Multilayer MNs, dissolvable MNs	PCL, PVP, PAM	Metformin, CaO2-HA NPs	Reduces the IL-6 level	Antibacterial, hypoglycemic, antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	81
	Double-layer MNs, dissolvable MNs	GelMA, PCL, gelatin	Metformin, PDA, O2	Reduces the expression levels of TNF-α	Ameliorating hypoxia, antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	224
	Double-layer MNs, dissolvable MNs	HA, CS, SF	TCH, DFO	Reduces the expression levels of TNF-α	Antibacterial, anti-inflammatory, promoting angiogenesis and collagen deposition	225
	Double-layer MNs, dissolvable MNs	Gel-CMC, HA	TCH, rh-EGF	TCH reduces the IL-1β, IL-6, and TNF-α levels	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	85
	Double-layer MNs, dissolvable MNs	HA, SA-g-PNIPAM	TCH, SOS	Reduces inflammatory infiltration	Antibacterial, anti-inflammatory, promoting cell proliferation, angiogenesis and collagen deposition	226
	Hydrogel MNs	AlgMA	TSA	TSA promotes the polarization of macrophages from M1 to M2, inhibits HDAC4 and decreases pro-inflammatory cytokines	Hemostatic, anti-inflammatory, promoting angiogenesis and collagen deposition	227
	Hydrogel MNs	PVA, HA, gelatin	6-Gingerol	6-Gingerol promotes the polarization of macrophages from M1 to M2 via an AMPK/mTOR pathway	Anti-inflammatory, promoting angiogenesis and collagen deposition	228
	Hydrogel MNs	PEG, sodium alginate	Erythromycin, vaccarin, demethylsuberosin, cyanidin	Promotes the polarization of macrophages from M1 to M2, reduces the expression levels of TNF-α and IL-1β, and increases the expression levels of IL-10	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis, re-epithelialization and collagen deposition	229
	Core–shell MNs, dissolvable MNs	SF	dBRD9, SAG	dBRD9 inhibits macrophage activation and reduces the expression levels of TNF-α, iNOS and STAT1	Anti-inflammatory, promoting re-epithelialization, collagen deposition, and angiogenesis.	230
	Core–shell MNs, dissolvable MNs	HA-β-CD, HAMA	MCC950, MG	MCC950 promotes the polarization of macrophages from M1 to M2 via inhibiting the NLRP3/IL-1β pathway and reduces the TNF-α and IL-6 levels	Antibacterial, anti-inflammatory, promoting angiogenesis, re-epithelialization and collagen deposition	231
	Dissolvable MNs	Pullulan	MOXNPs, LH, TH	Reduces the expression levels of TNF-α and IL-6	Hemostatic, analgesic, antibacterial, anti-inflammatory, promoting cell proliferation, angiogenesis and collagen deposition	232
	Dissolvable MNs	HA	NPF NPs	NPF NPs promote the polarization of macrophages from M1 to M2 via activating the insulin pathway, and reduce the IL-1β and IL-6 levels	Antibacterial, hypoglycemic, antioxidant, anti-inflammatory, promoting angiogenesis, re-epithelialization and collagen deposition	98
	Dissolvable MNs	PVA	Hb-RES NPs, ANW	Hb-RES NPs inhibit M1 macrophage activation	Antibacterial, hypoglycemic, ameliorating hypoxia, antioxidant, anti-inflammatory, promoting angiogenesis and re-epithelialization	96
	Dissolvable MNs	γ-PGA, ε-PLL	CGA, Sr^2+	Promotes the polarization of macrophages from M1 to M2	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis and cell proliferation	99
	Double-layer MNs, dissolvable MNs	PVA, HA	TA, Eu^3+	Promotes the polarization of macrophages from M1 to M2, reduces the expression levels of TNF-α, and increases the expression levels of TGF-β	Antibacterial, antioxidant, anti-inflammatory, promoting cell proliferation, angiogenesis and collagen deposition	95
	Dissolvable MNs	HA, PVA	RES MC, GEN	RES MC reduces the expression levels of TNF-α and IL-6	Antibacterial, antioxidant, anti-inflammatory, promoting re-epithelialization and collagen deposition	97
	Dissolvable MNs	HA, SOS	Quer-NCs, PDGF-BB	Promotes the polarization of macrophages from M1 to M2 and reduces the TNF-α and IL-6 levels	Antibacterial, anti-inflammatory, promoting angiogenesis and collagen deposition	100
	Hydrogel MNs	GelMA	PC	PC suppresses M1 macrophage activation and decreases pro-inflammatory cytokines via inhibiting the TLR4/MYD88 pathway	Anti-inflammatory	105
	Dissolvable MNs	HA	RY/LA	RY/LA promotes the polarization of macrophages from M1 to M2 via the NF-κB pathway	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	106
	Dissolvable MNs	CMCS, BSP	APB@Ber	Promotes the polarization of macrophages from M1 to M2 by curbing the ROS/NF-κB pathway and reduces the TNF-α and IL-6 levels	Hemostatic, antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	101
	Dissolvable MNs	HA	Nap@PLGA, rhCol III	Nap decreases local macrophage infiltration	Anti-inflammatory, enhancing cell proliferation, angiogenesis and collagen deposition	107
	Hydrogel MNs	HAMA	Res@PtZ-Z	Promotes the polarization of macrophages from M1 to M2 and reduces the TNF-α, IL-1βand IL-6 levels	Antibacterial, antioxidant, anti-inflammatory, promoting cell proliferation, angiogenesis and collagen deposition	233
Proteins	Hydrogel MNs	GelMA, AFPBA	G-Insulin	Reduces inflammatory infiltration	Hypoglycemic, anti-inflammatory, promoting collagen deposition	234
	Double-layer MNs, hydrogel MNs	PVAMA, PBA, QDL, OHD	Insulin, POGa	Reduces the TNF-α levels and inflammatory cell infiltration.	Antibacterial, hypoglycemic, anti-inflammatory, promoting angiogenesis, re-epithelialization and collagen deposition	111
	Hydrogel MNs	SF, PU, NIPAM	hEGF	Reduces the TNF-α and IL-6 levels	Anti-inflammatory, promoting re-epithelialization and collagen deposition	77
	Core–shell MNs, hydrogel MNs	HAMA, CMCS, SA	bFGF, GO-ASyycF	Promotes the polarization of macrophages from M1 to M2	Antibacterial, anti-inflammatory, promoting angiogenesis, re-epithelialization and collagen deposition	116
	Hydrogel MNs	HAMA, PVA	bFGF, minocycline	Reduces the expression levels of IL-6	Antibacterial, antioxidant, anti-inflammatory, promoting cell migration, angiogenesis and collagen deposition	217
	Dissolvable MNs	Sucralfate, PVP	IL-4	Promotes the polarization of macrophages from M1 to M2 via the JAK-STAT pathway	Anti-inflammatory, promoting cell proliferation, angiogenesis and collagen deposition	117
	Hydrogel MNs	1-RHC	PRP	Promotes the polarization of macrophages from M1 to M2	Antibacterial, anti-inflammatory, promoting angiogenesis, re-epithelialization and collagen deposition	235
	Double-layer MNs, dissolvable MNs	BS, HA, PVA, Alg	GOx, CAT	Promotes the polarization of macrophages from M1 to M2	Antibacterial, hypoglycemic, antioxidant, anti-inflammatory, promoting angiogenesis, re-epithelialization and collagen deposition	6
	Double-layer MNs, dissolvable MNs	PVA, GelMA	GOx, α-amylase, QHREDGS	Reduces the expression levels of TNF-α and IL-6	Antibacterial, hypoglycemic, anti-inflammatory, promoting angiogenesis and collagen deposition	119
Nucleic acids	Dissolvable MNs	SF, SilMA	miRNA-mDTC NPs, Mn-DCaO2 NPs, DFO	miRNA-147 reduces IL-6 and TNF-α levels via the NF-κB pathway and DA promotes M2 macrophage polarization and enhances IL-10 levels	Hemostatic, ameliorating hypoxia, antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	87
	Double-layer MNs, hydrogel MNs	HA, MXene	triplet mRNA, Ag-NPs	Growth factors reduce the expression levels of TNF-α	Antibacterial, anti-inflammatory, promoting cell proliferation, collagen deposition and angiogenesis	129
	Dissolvable MNs	HAMA	Co^2+, DNA	Reduces the expression levels of TNF-α and increases the expression levels of IL-10	Antibacterial, hypoglycemic, anti-inflammatory, promoting cell proliferation, angiogenesis and collagen deposition	132
Cells	Hydrogel MNs	HAMA	ADSCs	ADSC spheroids activate inflammatory signaling pathways	Promoting angiogenesis and collagen deposition	139
	Double-layer MNs, hydrogel MNs	GelMA-CS	KCs, FBs	Secretes cytokines and expected to promote M2 macrophage polarization	Antibacterial, anti-inflammatory, promoting cell proliferation, collagen deposition and angiogenesis	71
Exosomes	Hydrogel MNs	Functional DNA segments	H-EVs	Promotes the polarization of macrophages from M1 to M2, reduces the expression levels of IL-1β, and increases the expression levels of IL-10	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis, neurogenesis, re-epithelialization and collagen deposition	82
	Double-layer MNs, hydrogel MNs	GelMA, SilMA	MSC-exos, Ag-NPs	Promotes the polarization of macrophages from M1 to M2 and reduces the expression levels of IL-6	Antibacterial, anti-inflammatory, promoting angiogenesis and collagen deposition	148
	Hydrogel MNs	PVA	MSC-exos	Inhibits M1 macrophage polarization and reduces the expression levels of TNF-α	Anti-inflammatory, promoting angiogenesis and collagen deposition	236
	Dissolvable MNs	HA	UC-EVs, NBS-PB	Reduces the expression levels of IL-6 and increases the expression levels of IL-10	Antibacterial, anti-inflammatory, promoting cell proliferation, collagen deposition and angiogenesis	237
	Core–shell MNs, dissolvable MNs	HA, HAMA	Fe-MSC-NVs, PDA NPs	Promotes the polarization of macrophages from M1 to M2, reduces the expression levels of TNF-α and IL-6, and increases the expression levels of IL-10	Antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	88
	Double-layer MNs, hydrogel MNs	HAMA, PVA	MEs, PDA NPs	Promotes the polarization of macrophages from M1 to M2 and reduces the expression levels of TNF-α	Anti-inflammatory, promoting angiogenesis and collagen deposition	159
	Core–shell MNs, hydrogel MNs	HA, PFP	M2-EVs	Promotes the polarization of macrophages from M1 to M2 and reduces the expression levels of IL-6	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	238
	Dissolvable MNs	ADMMA-GEL	PLT-Exos	Promotes the polarization of macrophages from M1 to M2, reduces the expression levels of TNF-α and IL-6, and increases the expression levels of IL-10 and IL-4	Anti-inflammatory, promoting angiogenesis and collagen deposition	162
Metal ions	Dissolvable MNs	PLGA	Mg^2+, H2	Mg^2+ promotes the polarization of macrophages from M1 to M2 and reduces the expression levels of IL-1β and IL-6	Antioxidant, anti-inflammatory, promoting cell proliferation, angiogenesis and collagen deposition	166
	Double-layer MNs, dissolvable MNs	CS, PVP	Mg^2+, PNS	Mg^2+ promotes the polarization of macrophages from M1 to M2 and reduces the expression levels of TNF-α and IL-6	Antibacterial, anti-inflammatory, promoting angiogenesis, re-epithelialization and collagen deposition	164
	Hybrid-nested MNs, dissolvable MNs	CS, PVP, PLGA	Mg^2+, GA, Vn, W379 and QK peptides	Mg^2+ promotes the polarization of macrophages from M1 to M2	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	89
	Dissolvable MNs	PVA	SeC@PA	Promotes the polarization of macrophages from M1 to M2 via the JAK-STAT6 pathway, reduces the expression levels of TNF-α and IL-1, and increases the expression levels of IL-10 and IL-4	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	239
	Double-layer MNs, dissolvable MNs	HAMA	SeNPs@LAS, Fe3O4	Promotes the polarization of macrophages from M1 to M2	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	240
	Double-layer MNs, dissolvable MNs	GelMA, GelMA-PPy, PEGDA, HA-DA	Zn^2+, GA, DFO	Reduces the expression levels of IL-6	Hemostatic, antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	91
	Hydrogel MNs	GelMA, PEGDA, PANI	Zn^2+, TA	Reduces the expression levels of TNF-α and IL-6	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis, collagen deposition and re-epithelialization	94
	Dissolvable MNs	PVP	Zn^2+, CIP, GOx	Reduces inflammatory cell infiltration	Antibacterial, hypoglycemic, anti-inflammatory, promoting angiogenesis, collagen deposition and re-epithelialization	241
	Dissolvable MNs	HA	Zn^2+, Ce^3+/4+	Inhibits M1 macrophage polarization and reduces the expression levels of TNF-α and IL-6	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	169
	Dissolvable MNs	GMA-HA	Ce^3+/4+, CV	Reduces the expression levels of TNF-α and IL-6	Antibacterial, antioxidant, anti-inflammatory, promoting cell proliferation, angiogenesis and collagen deposition	172
	Dissolvable MNs	PVA, PVP	Ce^3+/4+, Metformin	Reduces the expression levels of TNF-α and IL-6	Antioxidant, anti-inflammatory, promoting angiogenesis, collagen deposition and re-epithelialization	242
	Dissolvable MNs	HA	Ce^3+/4+, VEGF	Promotes the polarization of macrophages from M1 to M2, reduces the expression levels of TNF-α, IL-1β and IL-6, and increases the expression levels of IL-4	Antioxidant, anti-inflammatory, promoting cell proliferation, angiogenesis and collagen deposition	170
	Hydrogel MNs	GelMA	Ce^3+/4+, taurine	Promotes the polarization of macrophages from M1 to M2, reduces the expression levels of IL-1β and IL-6, and increases the expression levels of IL-10	Antioxidant, anti-inflammatory, promoting cell proliferation, angiogenesis and collagen deposition	243
	Dissolvable MNs	γ-PGA	Ce^3+/4+, Ag^+, Si^2+	promotes the polarization of macrophages from M1 to M2 and reduces the expression levels of TNF-α, IL-1β and IL-6	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	171
	Dissolvable MNs	Lys-AFs, PVA	Ce^3+/4+, GOx, TA	Promotes the polarization of macrophages from M1 to M2 and reduces the expression levels of IL-6	Antibacterial, hypoglycemic, ameliorating hypoxia, antioxidant, anti-inflammatory, promoting cell proliferation, angiogenesis and collagen deposition	173
	Double-layer MNs, Dissolvable MNs	PVP, CBAA	CexMny MMON, Res@ZIF67	Promotes the polarization of macrophages from M1 to M2 and Reduces the expression levels of TNF-α, IL-1β and IL-6	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis, re-epithelialization and collagen deposition	244
	Double-layer MNs, hydrogel MNs	GelMA, MXene	Fe^2+/Fe^3+	Promotes the polarization of macrophages from M1 to M2	Antibacterial, ameliorating hypoxia, antioxidant, anti-inflammatory, promoting cell proliferation, angiogenesis and collagen deposition	174
	Double-layer MNs, dissolvable MNs	SilMA	PBNs, VEGF, Polymyxin	Promotes the polarization of macrophages from M1 to M2 and reduces the expression levels of TNF-α and IL-1β	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	175
	Hydrogel MNs	HAMA	PBNs, Taurine	Inhibits NET formation and promotes the polarization of macrophages from M1 to M2	Antioxidant, anti-inflammatory, promoting collagen deposition	176
	Dissolvable MNs	HAMA	MnO2, Cu^2+, PDA	Reduces inflammatory cell infiltration	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis, collagen deposition and re-epithelialization	177
	Dissolvable MNs	HAMA	MnO2, Cu^2+, TA	Reduces the expression levels of TNF-α, IL-1β and IL-6	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis, collagen deposition and re-epithelialization	93
Gas	Double-layer MNs, dissolvable MNs	PVP, PVA	H2, Co^2+	Promotes the polarization of macrophages from M1 to M2 and reduces the expression levels of IL-6	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis, collagen deposition and re-epithelialization	192
	Dissolvable MNs	PVA, HEMA, HMPP	H2S, CAT, PMB	Promotes the polarization of macrophages from M1 to M2 and reduces the expression levels of TNF-α	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis, collagen deposition and neurogenesis	195
	Dissolvable MNs	PEGDA, PEG	H2S, Zn^2+, GOx, Ta4C3 MXenes	Promotes the polarization of macrophages from M1 to M2, reduces the expression levels of TNF-α and IL-6, and increases the expression levels of IL-10	Antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis, re-epithelialization and collagen deposition	245
	Dissolvable MNs	HA	CO, GOx	Reduces inflammatory cell infiltration	Antibacterial, hypoglycemic, anti-inflammatory, promoting angiogenesis and collagen deposition	197
	Dissolvable MNs	Gelatin, polylysine	NO	Reduces the expression levels of TNF-α and IL-6	Antibacterial, anti-inflammatory, promoting angiogenesis and collagen deposition	246
	Dissolvable MNs	HA	NO, puerarin	Promotes the polarization of macrophages from M1 to M2 and reduces infiltration of neutrophils and the expression levels of TNF-α	Antibacterial, anti-inflammatory, promoting cell proliferation and angiogenesis	247
	Double-layer MNs, dissolvable MNs	HA, GelMA	NO, GOx, Zn^2+	Promotes the polarization of macrophages from M1 to M2, reduces the expression levels of TNF-α and IL-6, and increases the expression levels of IL-10	Antibacterial, hypoglycemic, anti-inflammatory, promoting angiogenesis	202
	Double-layer MNs, hydrogel MNs	GelTAMA, PEGDA	NO, O2	Promotes the polarization of macrophages from M1 to M2	Ameliorating hypoxia, antioxidant, anti-inflammatory, promoting neurogenesis, angiogenesis and collagen deposition	206
	Hydrogel MNs	PIL	O2	Reduces the expression levels of IL-6 and IL-1β	Ameliorating hypoxia, antibacterial, anti-inflammatory, promoting angiogenesis, collagen deposition and re-epithelialization	205
	Separable MNs, hydrogel MNs	GelMA, PVA	O2	Reduces inflammatory cell infiltration	Ameliorating hypoxia, antioxidant, anti-inflammatory, promoting angiogenesis, collagen deposition and re-epithelialization	204
	Dissolvable MNs	SilMA	O2, CAT, AgNPs	Promotes the polarization of macrophages from M1 to M2 and reduces the expression levels of TNF-α and IL-1β	Ameliorating hypoxia, antibacterial, antioxidant, anti-inflammatory, promoting angiogenesis and collagen deposition	248
	Hydrogel MNs	GelMA, PVA	O2	Reduces the expression levels of IL-6	Ameliorating hypoxia, anti-inflammatory, promoting angiogenesis, collagen deposition and re-epithelialization	249
	Dissolvable MNs	PVP	O2, H2O2	Reduces neutrophil infiltration	Ameliorating hypoxia, antibacterial, anti-inflammatory, promoting cell proliferation, angiogenesis and collagen deposition	250

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2. Impaired immune microenvironment of diabetic wounds

Chronic inflammation, a hallmark of diabetic wounds, is closely associated with the persistent dysregulation of the local immune microenvironment, ultimately impairing the transition to the proliferation/remodeling phase of wound healing. As a major pathophysiological mechanism, the sustained pro-inflammatory milieu is marked by the imbalanced infiltration of multifarious immune cells. The subsequently dysregulated immune cascade perpetuates a vicious cycle, exacerbated by continuous stimulation from pro-inflammatory cytokines, accumulation of metabolic by-products, and elevated oxidative stress.¹⁶ The highly pro-inflammatory microenvironment also impairs the proliferation and migration of keratinocytes, fibroblasts, and endothelial cells; reduces collagen deposition and re-epithelialization; and hampers granulation tissue formation and vascular maturation, thereby severely compromising wound healing (Fig. 2).¹⁷

Fig. 2 Impaired immune microenvironment of diabetic wounds. DCs, dendritic cells; TGF-β, transforming growth factor-beta; ECM, extracellular matrix; and NF-κB, nuclear factor kappa-B.

2.1. Dysregulated immune cell infiltration

The inflammatory phase of wound healing begins with the infiltration of immune cells into the wound site. Neutrophils are among the earliest and most abundant cells recruited to the lesion, peaking within 24 h. During the initial phase, neutrophils contribute to immune defense through phagocytosis and degranulation, while also releasing neutrophil extracellular traps (NETs) that aid in bacterial clearance and promote epidermal keratinocyte proliferation.¹⁸ However, sustained neutrophil infiltration and excessive NETs release exacerbate tissue inflammation. In addition, elevated protease activity results in excessive degradation of the extracellular matrix (ECM), collectively impairing the wound healing process.¹⁹

In addition to neutrophils, local mast cells respond rapidly to tissue damage. Pathological overactivation of mast cell degranulation is strongly associated with increased release of a range of mediators, including pro-inflammatory cytokines, vasodilation agents, vascular permeability factors, and proteases, which promote neutrophil chemotaxis.²⁰ This dysregulated response significantly impairs the precisely orchestrated spatiotemporal regulation of the healing response.²¹

As the inflammatory phase progresses, monocytes are recruited to the wound site within 48–96 h post-injury and primarily differentiate into pro-inflammatory M1 macrophages. These macrophages phagocytose invading pathogens, apoptotic neutrophils, and necrotic tissue fragments, while secreting a broad spectrum of pro-inflammatory cytokines and mediators to amplify the immune response. Following microbial clearance and debris removal, the wound microenvironment shifts to favor the polarization of M1 macrophages toward M2 macrophages. M2 macrophages secrete anti-inflammatory cytokines and growth factors that facilitate inflammation resolution, neovascularization, cell proliferation, and re-epithelialization. This phenotypic transition represents a pivotal turning point in wound healing, marking the shift from the inflammatory to the proliferative phase.⁴ In diabetic patients, chronic hyperglycemia induces systemic immune dysregulation even prior to injury, characterized by elevated levels of bone marrow-derived myeloid progenitors and circulating inflammatory monocytes, and sustained myelopoiesis following wounding.²² Epigenetic modifications induced by hyperglycemia, such as DNA methylation, histone methylation, and acetylation, promote M1 macrophage polarization.²³ Moreover, obesity, the strongest risk factor for type 2 diabetes, independently drives M1 polarization and pro-inflammatory cytokine production, contributing to a systemic low-grade inflammatory state.²⁴ Chronic infection in diabetic wounds further perpetuates the M1 macrophage phenotype.²⁵ Aberrant microenvironmental cues in diabetic wounds lead to prolonged M1 macrophage activation in the early stages and impaired transition to the M2 phenotype in later phases. This dysregulated immune response results in sustained inflammation and failure to establish a reparative microenvironment, ultimately hindering effective wound healing.

Natural killer cells (NK cells) are traditionally recognized for their cytotoxic activity against pathogens and tumor cells, but they also play regulatory roles in immune responses involved in physiological processes such as wound healing. During the inflammatory phase, NK cells accumulate at the skin wounds and contribute to a pro-inflammatory environment by releasing interferon-γ (IFN-γ), tumor necrosis factor-alpha (TNF-α), perforins, and granzymes. This heightened inflammatory response can hinder the wound healing process.²⁶ Recent studies have shown that targeted depletion of NK cells in diabetic wounds improves re-epithelialization and collagen deposition, indicating that elevated NK cell activity may be a contributing factor to impaired healing associated with diabetes.²⁷

Dendritic cells (DCs) are antigen-presenting cells that play a pivotal role in priming T-cell responses and maintaining tissue homeostasis by modulating both innate and adaptive immune responses.²⁸ In diabetes, plasmacytoid DCs undergo epigenetic alterations that result in increased production of interleukin (IL)-6, driving pro-inflammatory responses that impair wound repair in chronic diabetic wounds.²⁹ Enhancing the efferocytosis capacity of DCs has also been explored as a strategy to improve healing in diabetic wounds, offering valuable insights for future investigations into the role of DCs in wound healing.³⁰

T cells, emerging at a more advanced stage of the wound healing process, exert a significant regulatory influence on the local immune milieu. Cutaneous injuries can trigger the accumulation of activated CD4+ helper T cells, contributing to a pro-inflammatory microenvironment in diabetic wounds.³¹ Diabetic patients exhibit elevated levels of circulating pro-inflammatory T cells, which further impair the healing of lesions.³² Conversely, regulatory T cells (Tregs) facilitate wound repair by reducing IFN-γ production and limiting the accumulation of pro-inflammatory macrophages. Efficient recruitment of Tregs to the wound beds effectively suppresses local inflammation and promotes diabetic wound closure.³³

2.2. Continuous cytokine stimulation

Wound closure and repair are orchestrated by a sequential cascade of biological events, primarily mediated by cytokine signaling. The transient expression of pro-inflammatory cytokines activates immune responses that promote angiogenesis, fibroblast proliferation, and collagen synthesis. However, in diabetic wounds, persistent cytokine expression sustains chronic inflammation and hinders the infiltration and activity of anti-inflammatory cells, consequently inhibiting the transition from the inflammatory phase to tissue repair processes. During the initial phase of diabetic wound healing, platelets secrete key growth factors, including transforming growth factor-β (TGF-β) and the platelet-derived growth factor (PDGF), which facilitate the recruitment of neutrophils and monocytes.³⁴ In the inflammatory stage, the excessive infiltration of inflammatory cells generates elevated levels of pro-inflammatory cytokines, such as TNF-α, IFN-γ, IL-1β, IL-6, IL-8, IL-23, and monocyte chemoattractant protein-1 (MCP-1). These cytokines function as potent chemoattractants, amplifying inflammatory cell recruitment and prolonging their retention at the wound site. For instance, circulating monocytes differentiate into M1 macrophages upon activation by cytokines such as TNF-α and IFN-γ, thereby reinforcing a positive feedback loop that sustains macrophage polarization and perpetuates a chronic inflammatory milieu.³⁵ Furthermore, pro-inflammatory cytokines also participate in multiple signaling pathways that exacerbate inflammation. Recent evidence indicates that NETs can aberrantly activate the NOD-like receptor protein 3 (NLRP3) inflammasome in macrophages, driving elevated expression of IL-1β and IL-18, which in turn promote further M1 polarization and NET formation.³⁶ Similarly, hyperglycemia activates the Notch signaling pathway, enhancing the production of IL-6 and inducible nitric oxide synthase (iNOS), while suppressing the anti-inflammatory cytokine IL-10, further polarizing macrophages toward the M1 phenotype.³⁷

2.3. Excessive metabolic by-products

The non-enzymatic glycation of proteins upon exposure to elevated sugars leads to the formation of advanced glycation end products (AGEs), impairing wound healing by disrupting immune homeostasis.³⁸ The interaction of AGEs with their receptors (RAGEs) on endothelial cells, monocytes, and macrophages promotes intracellular reactive oxygen species (ROS) generation, which subsequently activates the nuclear factor kappa-B (NF-κB) signal pathway. This cascade enhances the expression of pro-inflammatory cytokines and proteases, while also promoting macrophage polarization toward the M1 phenotype.³⁹ Additionally, elevated AGE levels also impede the phagocytic capacity of macrophages, thereby sustaining a pro-inflammatory state,⁴⁰ and contribute to the degradation and dysfunction of the ECM.⁴¹

Matrix metalloproteinases (MMPs), secreted by immune cells, keratinocytes, and fibroblasts in response to cytokines and growth mediators including interferons, interleukins, EGF, and VEGF, are zinc-dependent endopeptidases that degrade and remodel the ECM components.⁴² In diabetic wounds, elevated glucose levels activate the extracellular signaling-related kinase/activator protein-1 signaling pathway, resulting in upregulated MMP expression, particularly matrix metalloproteinase-9 (MMP-9).⁴³ The disrupted balance of MMPs and their natural inhibitors—tissue inhibitors of MMPs (TIMPs) leads to ECM degradation, impaired collagen synthesis and granulation tissue formation.⁴⁴ Moreover, the breakdown products of the ECM influence immune cell behavior by modulating their activation, differentiation, and survival, thereby promoting further macrophage recruitment and amplifying the pro-inflammatory milieu within the wound.⁴⁵

2.4. Elevated oxidative stress

ROS, secondary metabolites generated through cellular processes such as aerobic respiration, immune responses, and intracellular signaling pathways, predominantly exist in the form of a superoxide anion (O₂˙⁻), hydroxyl radicals (˙OH), hydrogen peroxide (H₂O₂), and hypochlorous acid (HClO).⁴⁶ At physiological levels, ROS are essential mediators in normal wound healing, contributing to hemostasis, angiogenesis, and re-epithelialization.⁴⁷ However, excessive ROS production leads to oxidative stress, resulting in cellular damage to proteins, lipids, and DNA. This disruption contributes to impaired healing via inducing cell death and triggering deleterious processes such as necrosis, inflammation, and fibrotic scarring.⁴⁸

A hallmark of diabetic wounds is sustained oxidative stress, characterized by excessive ROS accumulation and a concurrent deficiency in antioxidants.⁴⁹ High glucose levels, AGEs, and activated immune cells collectively contribute to an oxidative wound microenvironment.^19,47,50 Hyperglycemia increases electron flux into the tricarboxylic acid cycle and impairs the activity of key intracellular antioxidant enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). This imbalance exacerbates ROS accumulation and activates the NF-κB signaling pathway in macrophages, driving their polarization toward the M1 phenotype and upregulating the expression of inflammatory genes.⁵¹ The excessive accumulation of ROS also impairs essential tissue repair processes such as angiogenesis, ECM remodeling, and re-epithelialization, thereby further delaying wound closure and tissue regeneration.⁵²

3. Engineering parameters of immunomodulatory microneedles

Immunomodulatory strategies using MNs aimed at reversing immune cell dysfunction, reprogramming macrophage phenotypes, reducing the concentration of pro-inflammatory cytokines, blocking the formation of metabolic by-products, and restoring oxidative equilibrium are of great significance for re-establishing the immune homeostasis and promoting effective diabetic wound healing. The design parameters of MNs extend beyond the selection of tip materials to include critical structural attributes (Fig. 3). A comprehensive understanding of these parameters and their functional implications is essential for optimizing MNs’ performance in advanced therapeutic applications.

Fig. 3 Engineering parameters of immunomodulatory MNs for diabetic wound healing.

3.1. Material manipulation

A diverse array of both natural and synthetic materials have been utilized in the preparation of MNs. To enable precise modulation of immune responses, engineered biomaterials with intrinsic anti-inflammatory properties have been developed, aiming to mediate specific interactions with the immune system.⁵³ Key parameters, such as drug-loading capacities, mechanical strength, degradation characteristics, stability, and immunomodulatory potency, can be finely tuned through strategies such as chemical modification, material integration, and controlled cross-linking degree.

As a biodegradable polymer suitable for MN fabrication, poly (γ-glutamic acid) (γ-PGA) exhibits SOD, GPx, and CAT-like activities, enabling it to function as an antioxidant that reduces ROS and exerts anti-inflammatory effects.⁵⁴ Gan et al. introduced a highly biocompatible, water-soluble γ-PGA-based MN patch encapsulating glucose oxidase (GOx)-loaded MXene to promote diabetic wound healing.⁵⁵ The integration of MXenes not only enhances drug-loading capacity but also bolsters MN mechanical strength. Both γ-PGA and MXenes possess antioxidant properties by scavenging ROS, which contributes to synergistic immunomodulatory activity, thereby promoting a phenotypic shift from pro-inflammatory M1 to anti-inflammatory M2 macrophages, ultimately restoring the impaired immune microenvironment characteristic of diabetic wounds. Upon near-infrared (NIR) light exposure, MXenes induce mild hyperthermia, enhancing GOx catalytic activity to reduce local glucose concentrations and thereby facilitating cell proliferation, migration, angiogenesis, and tissue remodeling. Similarly, silk sericin, a group of polypeptides and a major component of silk fibers, possesses low immunogenicity, inherent cell-adhesive properties, biodegradability, and multiple bioactivities associated with tissue regeneration, including antioxidant, anti-inflammation and cell proliferation. Moreover, the abundance of amino acids and functional side chains in sericin offers numerous sites for the chemical modification, enabling the development of new functionalities.⁵⁶ Leveraging these properties, Liu et al. developed a ROS-responsive, O₂-generating MN platform (HFSVM) by cross-linking dopamine-functionalized sericin (SDA) with 4-amino-3-fluorophenylboronic acid-functionalized hyaluronic acid (HA-FPBA), and loading the construct with verteporfin (Fig. 4(A)).⁵⁷ As the major component of HFSVM, the dopamine modification endowed sericin protein with enhanced antioxidant activity to rapidly react with ROS and trigger O₂ generation, resulting in decreased expression of pro-inflammatory cytokines and enhanced tissue oxygenation. Furthermore, glucose competitively interacts with FPBA, leading to boronate ester dissociation and triggering verteporfin release, which facilitates scarless re-epithelialization.

Fig. 4 Material manipulation and structural regulation approaches of immunomodulatory microneedles. (A) Schematic illustration of the fabrication of an oxygen-generating microneedle platform (HFSVM), achieved through boronate ester-mediated cross-linking of dopamine-functionalized sericin (SDA) and 4-amino-3-fluorophenylboronic acid-functionalized hyaluronic acid (HA-FPBA), with the loading of verteporfin. Reproduced from ref. 57 with permission from John Wiley and Sons, copyright 2024. (B) Schematic illustration of how heparin-coated porous microneedles (HPMN) bound and sequestered chemokines, and attracted inflammatory monocytes/macrophages into HPMN, before removing HPMN from the wound to promote tissue healing. Reproduced from ref. 62 with permission from John Wiley and Sons, copyright 2024. (C) Schematic illustration of the structure of the microneedle patch with programmed functions (PF-MN), composed of a ROS-degradable poly (vinyl alcohol) shell (VP@PVA shell) loaded with verteporfin (VP), and a core component made of crosslinked heparin (cHP core) for cytokine binding. Reproduced from ref. 63 with permission from Springer Nature, copyright 2023. (D) Schematic illustration of the structure of the porcupine quill-like microneedles, composed of a hydrogel back patching loaded with polydopamine (PDA), and polycaprolactone tips loaded with sodium hyaluronate-modified CaO₂ nanoparticles (CaO₂-HA NPs) and metformin. Reproduced from ref. 81 with permission from Elsevier, copyright 2023. (E) Schematic illustration of the double bionic and large deformation structures of polypeptide deoxyribonucleic acid hydrogel microneedles (P-DNA gel MNs), as well as the overall evaluation of the wound microenvironment in diabetes after treatment with P-DNA gel MNs/H-EVs hypoxia. Reproduced from ref. 82 with permission from John Wiley and Sons, copyright 2023.

Certain polysaccharides, such as konjac glucomannan (KGM), present mannose units on the surface that mimic endogenous ligands and effectively engage mannose receptors, thereby promoting macrophage polarization toward the anti-inflammatory M2 phenotype.⁵⁸ While the natural polymer demonstrates excellent biocompatibility and biodegradability, making it a promising functional drug carrier, its inherent high viscosity poses significant formulation challenges. This viscosity hampers the preparation of highly concentrated aqueous solutions with sufficient fluidity for MN fabrication. To address this limitation without damaging its mannose units, oxidative modification of KGM has been employed as an effective strategy to reduce viscosity and enhance solubility.⁵⁹ A multifunctional MN patch composed of oxidized konjac glucomannan (OKGM) and encapsulating a copper-gallate metal–organic framework (CuGA-MOF) was developed for diabetic wound healing.⁶⁰ Upon insertion into the dermis, the MNs release Cu²⁺ and gallic acid (GA), where Cu²⁺ serves as an antibacterial agent and angiogenic stimulator, while GA scavenges excess intracellular ROS, thereby mitigating oxidative-induced inflammation in macrophages. Notably, the OKGM matrix as a fabrication material of MNs is more than a carrier of drugs, which itself could also actively contribute to immunomodulation by promoting M2 macrophage polarization.

Glycosaminoglycans (GAGs), key components of the ECM, such as chondroitin sulfate and heparin, have been reported to sequester pro-inflammatory cytokines through electrostatic interactions between their negatively charged sulfate groups and the positively charged amino acid residues of cytokines.⁶¹ Inspired by the concept of extracting fluid biomarkers from the wound bed using MNs, Le et al. designed sponge-like chemokine-sequestrating MNs (HPMN) for targeted therapy of inflamed diabetic tissue (Fig. 4(B)).⁶² Carboxyl groups on MNs react with amines on star-shaped polyethylene glycol (StarPEG) to immobilize the heparin/StarPEG network on the MN surface. The heparin-to-StarPEG molar ratio is optimized for preferential binding of multiple inflammatory chemokines, especially MCP-1. The localized accumulation of MCP-1 within the HPMN establishes a chemokine gradient that actively recruits inflammatory monocytes into the porous MN matrix. Subsequent removal of the MNs effectively eliminates both the sequestered chemokines and infiltrated monocytes from the wound site. Our group developed a core–shell MN patch with programmed functionalities (PF-MNs) designed to dynamically modulate the wound immune microenvironment across different healing phases (Fig. 4(C)).⁶³ The ROS-sensitive poly(vinyl alcohol) shell (VP@PVA) loaded with verteporfin produces ROS under laser irradiation to eliminate multidrug-resistant bacterial biofilm during the early inflammatory stage. To facilitate the transition from inflammation to proliferation, the VP@PVA shell was specifically engineered with tailored degradation characteristics. This design facilitates the sequential degradation of the PVA shell for VP release, followed by the exposure of the MN core composed of crosslinked heparin (cHP), which subsequently scavenges excess pro-inflammatory cytokines—including IFN-γ, MCP-1, TNF-α, IL-1β, and IL-6—during the later stages of inflammation. Moreover, the cHP core exhibits excellent structural stability, with minimal degradation observed over a 96-hour period. This combined antibacterial and anti-inflammatory action facilitates macrophage polarization from the pro-inflammatory M1 phenotype to the reparative M2 phenotype, thereby promoting effective diabetic wound healing. Further studies are warranted to optimize the inflammatory cytokine adsorption capacity of GAG-based MNs and to determine appropriate dressing frequency for maximal therapeutic efficacy and clinical translation. Additionally, current research on GAG-based MNs is largely limited to a few conventional GAGs. Exploration of other sources of GAGs, such as natural snail glycosaminoglycan with favorable biocompatibility and immunomodulatory properties, holds promise. However, the inherent electrostatic interactions of negatively charged polysaccharides may also non-selectively bind beneficial positively charged molecules, including anti-inflammatory mediators such as IL-10.^64,65 Thus, strategies to minimize these unintended depletions remain a critical challenge given the complex roles of inflammatory mediators in wound healing.

3.2. Structural regulation

The structural parameters of MNs, including base size, tip radius, needle length, density, shape, surface characteristic, and mechanical strength,⁶⁶ directly influence their immunomodulatory performances. In the context of diabetic wounds, MN tips serve as self-regenerative micro-centers of the skin, and their distribution density plays a pivotal role in regulating the spatial dynamics of immunomodulatory mediators and the behavior of resident biological cells.^67–69 High needle density increases MNs’ specific surface area, enhancing bioactive factor release and tissue contact, while also improving mechanical resistance to deformation induced by cell migration and growth. This, in turn, supports better immune microenvironment regulation and tissue regeneration. However, excessive needle density may increase surface hydrophobicity, potentially inhibiting directional cell migration and proliferation.^70,71 For instance, bilayer MNs loaded with keratinocytes and dermal fibroblasts have been employed to simulate the layered architecture of natural skin, delivering two cell types in a temporally and spatially controlled manner.⁷¹ To optimize immune regulation and regenerative efficacy, the interplay between MN density and tissue response is systematically evaluated. By testing various inter-needle spacings (2000, 1500, 1000, and 500 μm), it is observed that MN density had a minimal impact on cell proliferation at the needle tip. However, cell migration is significantly enhanced at spacings of 1500, 1000, and 500 μm compared to 2000 μm, with the greatest mobility observed at 1000 μm.

The MN platforms usually suffer from inadequate tissue adhesion, primarily arising from conventional micromanufacturing techniques that produce MNs with smooth, conical sidewalls, which inherently exhibit poor adhesion and typically require auxiliary fixation.^72,73 Nonetheless, the use of chemical adhesives or mechanical fastening methods, such as tapes or staples, may introduce toxicity or mechanical trauma, further delaying wound healing.^74,75 To address this challenge, the development of advanced MN patches with tailored structures and matrix compositions offers a promising strategy. Numerous natural microstructures, such as eagle claws,⁷⁶ shark teeth⁷⁷ and octopus suckers,⁷⁸ have inspired the development of multifunctional bioinspired MNs designed to enhance adhesion and mitigate inflammation.^79,80 Drawing inspiration from the barb-like microstructure of porcupine quills, Liu et al. engineered a trilayer MN dressing that mimics the mechanical anchoring of quills (Fig. 4(D)).⁸¹ This dressing comprises a flexible, adhesive hydrogel backing (polyacrylamide–polydopamine/Cu²⁺) with inherent antibacterial properties and MN tips composed of polycaprolactone/polyvinylpyrrolidone (PCL/PVP), which are loaded with the hypoglycemic agent metformin and sodium hyaluronate-modified CaO₂ (CaO₂–HA) nanoparticles. Upon decomposition, these nanoparticles generate H₂O₂, conferring antibacterial, antioxidant, and O₂-releasing function. Zhou et al. developed polypeptide–DNA hydrogel MNs (P-DNA gel MNs) incorporating functional DNA segments and extracellular vesicles (EVs) into a 3D-printed mold, using a combination of DNA base pairing, chemical crosslinking, and physical entanglement for assembly (Fig. 4(E)).⁸² Inspired by natural structures such as crab claws and shark microgrooves, the MN design exhibits superior mechanical performance, including enhanced skin penetration, grip strength, tissue adhesion, and structural stability. Additionally, MNs display high deformability, drawing inspiration from traditional Chinese paper-cutting techniques, which helps mitigate skin tension and prevents wound rupture or expansion during the healing process. The antibacterial polypeptide–DNA hydrogel serves as a sustained-release matrix for EVs, endowing the system with multifunctional bioactivities, including antioxidative capacity, immunomodulation via macrophage polarization, and promotion of angiogenesis and neurogenesis.

In addition to surface morphological modifications, internal structural designs have also been integrated into MNs. Chitosan fiber-reinforced silk fibroin hydrogel MN patches were designed to achieve stable tissue adhesion.⁸³ The incorporation of highly hygroscopic chitosan fibers improves the swelling capacity of MNs, resulting in an uneven swollen structure which mechanically interlocks with surrounding tissues. Moreover, silk fibroin contributes inherent bioadhesiveness, while the chitosan fibers augment the stiffness of MNs upon swelling, resulting in improved adhesion to tissue. This dual-phase release profile leads to superior anti-inflammatory effects and prolonged therapeutic efficacy.

4. Therapeutic delivery for immune regulation

MN patches have emerged as a promising platform for diabetic wound treatment by enabling localized delivery of therapeutic agents directly to the wound site. This targeted approach enhances therapeutic efficacy while minimizing side effects. In the context of immune modulation, MN-based systems are being explored for the delivery of a diverse range of anti-inflammatory agents, including small molecules, proteins, nucleic acids, cells, exosomes, inorganic materials, gases, etc. By tailoring the degradation properties of MN materials, these systems enable temporally controlled and sustained drug release, facilitating deep-tissue penetration and maintaining higher local concentrations of therapeutic agents. Additionally, integrated MN platforms that combine drug delivery with physical stimuli, such as electrical/light stimulation, represent a novel synergistic approach. Ongoing advancements in the design of immunomodulatory MNs continue to refine their functionality, offering increasingly precise and effective strategies for diabetic wound management.

4.1. Small molecules

The treatment of inflammatory wounds necessitates the judicious selection of anti-inflammatory agents. Tetracycline hydrochloride (TCH) has been shown to inhibit metalloproteinases and reduce the production of pro-inflammatory cytokines by neutrophils, thereby exhibiting anti-inflammatory, bactericidal and antioxidant effects.⁸⁴ Liu et al. developed multifunctional double-layer MNs, comprising a hyaluronic acid (HA) substrate loaded with TCH and gelatin–carboxymethyl chitosan tips encapsulating recombinant human epidermal growth factor (rh-EGF) (Fig. 5(A)).⁸⁵ A burst release of TCH during the early wound–healing phase facilitates immediate antibacterial action and effective attenuation of inflammation and oxidative stress. Subsequently, the sustained, deep-tissue release of rh-EGF promotes angiogenesis and ECM formation during the proliferative phase. The spatially and temporally coordinated release strategy demonstrates a synergistic therapeutic effect, markedly enhancing diabetic wound healing outcomes.

Fig. 5 Small molecule and protein delivery for immune regulation. (A) Schematic representation of the sequential drug release of the double-layer drug-loaded microneedles to tackle the distinct key issues during the different stages of diabetic wound healing. Reproduced from ref. 85 with permission from John Wiley and Sons, copyright 2023. (B) Schematic illustration of the construction of an ASHR microneedle patch, composed of Au nanospheres (AS) and hemoglobin (Hb)–resveratrol (RES) nanoparticles (HR). Reproduced from ref. 96 with permission from John Wiley and Sons, copyright 2025. (C) Schematic illustration of the construction of the strontium polyphenol network microneedle patch (SrC-MPNs@MN-PP), as well as the therapeutic mechanism for promoting diabetic wound healing. Reproduced from ref. 99 with permission from Elsevier, copyright 2024. (D) Schematic illustration of the mechanism of sucralfate microneedles to accelerate wound healing, including reprogramming macrophage polarization thereby boosting the local production of growth factors (GFs) in the inflammation stage, as well as preventing GF degradation, thereby enhancing cell proliferation and angiogenesis in the proliferation stage. Reproduced from ref. 117 with permission from Elsevier, copyright 2024. (E) Schematic illustration of functions of bilayered biohybrid microneedles (BCHM) in accordance with the spatial division to promote diabetic wound healing, including enhancing angiogenesis, strengthening re-epithelialization, alleviating chronic inflammation, and suppressing bacterial infection. Reproduced from ref. 6 with permission from John Wiley and Sons, copyright 2023.

Natural polyphenols are well recognized for their potent antioxidant activity, primarily through free radical scavenging, as well as their anti-inflammatory and wound healing properties mediated via intracellular signaling pathways that modulate immune responses.⁸⁶ Representative polyphenols, including dopamine,^87,88 GA,^89–91 epigallocatechin gallate,^83,92 tannic acid (TA),^93–95 resveratrol,^96,97 protocatechualdehyde,⁹⁸ chlorogenic acid (CGA),⁹⁹ and some flavonoids^100–102 have been incorporated into MNs to exert an immunomodulatory effect that support diabetic wound healing. The abundant phenolic hydroxyl groups in polyphenols enable strong interactions with diverse small molecules or polymers, facilitating the formation of stable and uniform structures through mechanisms such as metal coordination, hydrogen bonding, covalent bonding and electrostatic interactions.^96,98,99,103 For example, a biodegradable MN system for the co-delivery of Au nanowire (ANW) and hemoglobin-resveratrol nanoparticles (Hb-RES NPs) was developed (Fig. 5(B)).⁹⁶ Through hydrogen bonding and π–σ and π–alkyl interactions, the self-assembled Hb-RES NPs, composed of O₂-carrying Hb and anti-inflammatory RES, effectively alleviate hypoxia, scavenge ROS and promote macrophage polarization toward the M2 phenotype. Simultaneously, the intrinsic GOx-like activity of ANWs facilitates sustained glucose depletion and antibacterial effects, further enhancing angiogenesis and re-epithelialization. CGA, a bioactive dietary polyphenol found in various plants, possesses potent anti-inflammatory, antioxidant, and antibacterial properties.¹⁰⁴ Li et al. developed self-assembling strontium-polyphenol networks (SrC-MPNs) by coordinating CGA with Sr²⁺ via catechol-ion interactions, resulting in enhanced structural stability (Fig. 5(C)).⁹⁹ Then, the MNs (SrC-MPNs@MN-PP) incorporated these SrC-MPNs are formulated with γ-PGA and epsilon-poly-L-lysine (ε-PLL), materials known for their robust antibacterial activity, exhibiting deep skin penetration, superior moisture retention, and sustained drug release capabilities. Within the wound environment, CGA released from SrC-MPNs neutralizes ROS and promotes macrophage polarization toward the M2 phenotype, while Sr²⁺ contributes to angiogenesis.

Although numerous small anti-inflammatory molecules exhibit potent pharmacological activities, their clinical utility is often hindered by poor water solubility and low bioavailability, which limit their pharmacokinetic performance and in vivo efficacy. To overcome these challenges, a variety of encapsulation strategies, such as liposomes,¹⁰⁵ polymeric micelles,^97,106 nanocrystals,¹⁰⁰ and nanoparticles,^101,107 have been employed to load these small molecules into MNs. For example, Li et al. encapsulated lipophilic resveratrol in polymeric micelles (RES MC), incorporated into HA-based MN tips.⁹⁷ The hydrophilic hydroxyl and carboxyl groups in HA facilitate localized and sustained delivery of RES MC to pathological sites, significantly reducing inflammation. In parallel, the incorporation of the antibiotic gentamicin into the PVA base imparts strong antibacterial activity, synergistically accelerating wound closure. Similarly, Liu et al. developed composite MNs embedding Astragalus polysaccharide (APS) nanoparticles loaded with Baicalein (Bai) and Berberine (Ber)—key bioactive compounds in traditional Chinese medicine known for their antioxidant, anti-inflammatory, and antimicrobial properties.¹⁰¹ By integrating hemostatic white peony polysaccharide and antimicrobial carboxymethyl chitosan into the MN matrix, the formulation not only enhances the intrinsic biological functions and mechanical strength of the MNs but also ensures stable adhesion and efficient nanoparticle dispersion. This system exerts potent immunomodulatory effects via downregulating ROS-activated NF-κB pathways, thereby promoting tissue regeneration.

4.2. Proteins

Protein-based therapeutics have garnered increasing attention and offered several advantages over traditional small molecule drugs, including high affinity, potency and specificity, and potent biological activity at low dosages, while demonstrating low toxicity and minimal adverse effects.¹⁰⁸ Insulin, the first approved therapeutic protein, has been widely recognized for its role in glucose metabolism but also exhibits significant wound–healing properties by promoting cell proliferation and protein synthesis.¹⁰⁹ Notably, insulin contributes to immune regulation not only indirectly—by lowering the blood glucose level and thereby suppressing inflammation—but also directly, through its interaction with immune cells to exert anti-inflammatory effects.¹¹⁰ An insulin-encased MN patch employing phenylboronic acid (PBA) as a glucose-responsive moiety was fabricated to regulate the immune environment with these two pronged approach.¹¹¹ Under hyperglycemic conditions, PBA forms reversible glucose–boronic acid complexes, enabling controlled and responsive release of insulin. Leveraging the broad-spectrum antimicrobial and pro-angiogenic properties of other components, in vivo studies demonstrate that the MN system significantly mitigates inflammation and accelerates wound regeneration in diabetic models. However, prolonged insulin administration would carry risks such as hypoglycemia, insulin resistance, and adipose tissue atrophy. To address these challenges, insulin-related protein therapeutics have shown promise in promoting diabetic wound healing through immune modulation. The integration of biomimetic, glucose-responsive protein drugs with MN platforms represents a promising strategy for next-generation diabetic wound therapies.

Cytokines are critical signaling molecules that orchestrate cellular behaviors and functions throughout various stages of wound repair, making them promising therapeutic agents for modulating immune responses.¹¹² Among them, interleukin-4 (IL-4) is one of the most prominent anti-inflammatory cytokines that can promote M2 macrophage polarization and enhance angiogenesis.¹¹³ Additionally, basic fibroblast growth factor (bFGF), a potent mitogenic growth factor, not only stimulates re-epithelialization and angiogenesis,¹¹⁴ but also contributes to the attenuation of inflammation.¹¹⁵ A versatile hyaluronic acid methacrylate (HAMA)/carboxymethyl chitosan (CMCS) core–shell MN patch has been developed for sustained and controlled release of bFGF.¹¹⁶ The locally released bFGF notably facilitates the polarization of macrophages toward the M2 phenotype, augmenting angiogenesis and collagen synthesis. To accommodate the complex, dynamic demands across the different stages of wound healing, Le et al. proposed a dual-stage combinatorial cytokine strategy using IL-4-loaded dissolvable MNs fabricated with bioactive sucralfate—a material shown to preferentially bind growth factors such as bFGF and IL-4 over pro-inflammatory cytokines present in wounds (Fig. 5(D)).¹¹⁷ In the initial stage, sucralfate MNs enhance IL-4 bioactivity, effectively reprogramming M1 macrophages into pro-regenerative M2 macrophages by activating the Janus kinase-signal transducer and activator of the transcription (JAK-STAT) pathway, thereby boosting the local production of growth factors. In the subsequent stage, sucralfate's binding affinity sterically protects and stabilizes endogenous growth factors, preventing proteolytic degradation and extending their biological activity. This cascade ultimately enhances cell proliferation, angiogenesis, and wound closure.

Enzymes, essential biocatalysts in biological reactions, possess high catalytic activity, substrate specificity, and biocompatibility. GOx, which catalyzes the oxidation of glucose to gluconic acid and H₂O₂, simultaneously achieves glycemic control and antibacterial effects.¹¹⁸ Yu et al. devised a MN-based reaction system incorporating GOx to alleviate inflammation driven by hyperglycemia and bacterial infections in diabetic wounds.¹¹⁹ However, paradoxically, the H₂O₂ generated by GOx can exacerbate oxidative stress and inflammation.¹²⁰ CAT, a key endogenous antioxidant enzyme, along with SOD and GPx, plays a vital role in decomposing H₂O₂ into water and O₂.¹²¹ A bilayered biohybrid MN-based dressing (BCHM) that co-encapsulates GOx and CAT was designed for enhanced diabetic wound healing (Fig. 5(E)).⁶ In the exterior layer, GOx immobilized within an alginate hydrogel is integrated into a bromeliad leaf-inspired substrate featuring natural photosynthetic and self-drainage capabilities. This configuration facilitates local O₂ generation, enhances GOx activity for glucose degradation, and promotes both angiogenesis and surface bacterial clearance. The inner layer features MNs infused with CAT, which replenishes depleted intracellular antioxidant capacity, prevents ROS-induced macrophage polarization toward the pro-inflammatory M1 phenotype, and alleviates chronic inflammation.

Although MN-based transdermal patches enable controlled and sustained delivery of proteins, several critical concerns remain for clinical translation. Manufacturing, storage, and administration processes of protein-loaded MNs are often hindered by protein aggregation, degradation, denaturation, bioactivity loss, and suboptimal pharmacokinetics. To improve protein stability within the wound environment, various approaches including chemical modification, protein engineering, and carrier optimization should be explored. In addition, safety considerations of protein-based drugs, including off-target effects and immunogenicity of protein therapeutics due to activation of innate immune responses, may compromise therapeutic efficacy and cause adverse side effects.¹²² Despite notable advances in protein engineering, delivery technologies, and manufacturing processes aimed at mitigating these issues, current research on protein-based MNs tends to focus primarily on therapeutic outcomes, often neglecting the inherent limitations of protein drugs. These challenges warrant comprehensive investigation through systematic experimental studies in future research.

4.3. Nucleic acids

MN technology offers a promising platform for targeted gene therapy in diabetic wound healing. The cell membrane phospholipid bilayer typically possesses a negative charge, rendering the cellular entry of RNA molecules challenging due to the negatively charged phosphate groups on the RNA backbone. Consequently, positively charged delivery systems like cationic lipid/polymer-based nanoparticles have been extensively employed to circumvent various physiological barriers associated with naked RNA molecules, including nuclease degradation, rapid clearance by the mononuclear phagocyte system, inefficient cellular uptake, and poor endosomal escape.^123,124 Given the high ROS levels in an inflammatory microenvironment, optimal microRNA (miRNA) delivery systems must protect against oxidative damage and enzymatic degradation while ensuring targeted delivery, efficient cellular uptake, and successful endosomal escape.¹²⁵ To this end, Ran et al. developed dual-modular MNs featuring distinct degradation rates for sequential drug release tailored into different wound healing stages (Fig. 6(A)).⁸⁷ The fast-release module, based on silk fibroin, delivers miRNA-147-loaded nanoparticles (miRNA-mDTC NPs) formulated from quaternized chitosan (for superior endosomal escape efficiency), D-mannose (for macrophage targeting), and dopamine (for enhanced internalization while safeguarding from oxidative stress and RNase degradation). These NPs demonstrate efficient macrophage uptake, lysosomal escape, and miRNA transfection, leading to reduced IL-6 and TNF-α levels via NF-κB inhibition. Dopamine further promotes M2 macrophage polarization and increases IL-10 expression. The slow-release module, composed of methacrylated silk fibroin and deferoxamine, supports angiogenesis and tissue regeneration.

Fig. 6 Nucleic acid and cell delivery for immune regulation. (A) Schematic diagram of the anti-inflammatory mechanism of miRNA-147-loaded nanoparticles (miRNA-mDTC NPs), which demonstrate high endocytosis efficiency and efficiently transfect miRNA-147 to macrophages, inhibiting the nuclear factor (NF)-κB signaling pathway, consequently reducing IL-6 and TNF-α levels. Reproduced from ref. 87 with permission from John Wiley and Sons, copyright 2024. (B) Schematic illustration of the mechanism of the MXene hydrogel microneedles loaded with biomimetic triplet mRNA formulation (TM) for diabetic wound repair. Under NIR irradiation, TM is released and expresses platelet-derived growth factor (PDGF), fibroblast growth factor-7 (FGF-7), and vascular endothelial growth factor (VEGF). Reproduced from ref. 129 with permission from John Wiley and Sons, copyright 2024. (C) Schematic illustration of the preparation of cobalt pyrophosphate/DNA (Co₂PPi/DNA) nanocomposite, as well as the treatment of infected diabetic wounds via a systemic-local integrated strategy. Reproduced from ref. 132 with permission from John Wiley and Sons, copyright 2025. (D) Schematic illustration of the design of multi-island double-layered microneedle (MDMN) loaded with keratinocytes (KCs), fibroblasts (FBs), and chitosan, as well as the application of diabetic full-thickness wounds via mimicking the natural skin structure. Reproduced from ref. 71 with permission from Elsevier, copyright 2024. (E) Schematic illustration of the fabrication of the microfluidic-templating stem cell spheroid encapsulated microneedle (MN@SPs) patch, as well as its application in diabetic wound treatment. Reproduced from ref. 139 with permission from John Wiley and Sons, copyright 2023.

In addition to miRNA-based strategies, messenger RNAs (mRNAs) encoding anti-inflammatory or pro-regenerative proteins, such as IL-4,¹²⁶ CXCL12¹²⁷ and VEGF,¹²⁸ have shown potential in diabetic wound treatment. Wang et al. developed MXene-based hydrogel MNs to deliver a triplet mRNA cocktail (PDGF, FGF-7, and VEGF), enabling coordinated growth factor expression and enhanced tissue adaptation (Fig. 6(B)).¹²⁹ The biomimetic triplet mRNA formulation is encapsulated within lipid nanoparticles (LNPs) utilizing a microfluidic platform, thereby addressing challenges related to low physiological stability and suboptimal cellular internalization efficiency. The photothermal properties of MXenes allow controlled mRNA release, promoting angiogenesis and reducing TNF-α expression. In vivo results show superior healing outcomes compared to traditional delivery routes and monovalent formulations. Future designs could incorporate programmable mRNA formulations and cell-specific ligands to enable targeted, phase-specific modulation of the wound microenvironment.¹³⁰

Aptamers are single-stranded functional oligonucleotides that typically exhibit notable chemical stability and lack immunogenicity, and are capable of binding to target molecules with remarkable specificity and affinity.¹³¹ Qian et al. proposed a hierarchical cobalt pyrophosphate/DNA nanocomposite (Co₂PPi/DNA NF) crafted from the glucagon receptor (GCGR) aptamer and Co₂PPi nanosheets via a coordination-driven self-assembly strategy, which was subsequently dispersed into a dissolvable MN patch to enhance bioavailability (Fig. 6(C)).¹³² The GCGR aptamer incorporated within the nanoformulation exhibits superior nuclease resistance and sustained hepatic accumulation, primarily due to the dense Co₂PPi crystals that effectively limit nuclease accessibility and safeguard DNA from degradation, thereby guaranteeing the bioactivity of the DNA aptamer against the GCGR. Furthermore, Co₂PPi/DNA NFs could dissociate in an acidic environment that simulates the microenvironment of diabetic wound infections, promising to facilitate the sustained release of biofunctional components critical for enhancing wound healing. Upon application to diabetic wounds, the released nanocomposites dissociate in the wound for the sustained release of Co²⁺ ions and the GCGR aptamer. Co²⁺ ions eliminate colonized bacteria and stimulate angiogenesis, meanwhile, after circulating to the liver, the aptamer reduces blood glucose levels by binding to the hepatocyte GCGR. Significantly, this hypoglycemic effect promotes antibacterial and pro-angiogenic efficacy and alleviates the inflammatory responses as well, remodeling the local pathological microenvironment by systemic hyperglycemia regulation.

Despite considerable advancements, the safety profiles of nucleic acid-based therapeutics still require thorough assessment, particularly regarding immunogenicity and off-target effects—aspects that remain largely neglected in contemporary MN-mediated nucleic acid therapy.^124,133 For instance, RNA delivery platforms like LNPs, while effectively shielding RNA payloads from degradation and promoting cellular internalization, may inadvertently elicit immune recognition, consequently activating pro-inflammatory cascades and immune cell responses. Additionally, prolonged immune stimulation from either the delivery vehicle or RNA itself can potentially induce cellular or tissue toxicity, thereby raising important considerations regarding long-term safety for widespread clinical implementation.¹²⁴

4.4. Cells

MN-mediated cell therapy enables precise, sustained delivery of therapeutic cells via a minimally invasive and self-administrable platform. However, it presents formidable challenges for MN systems, particularly regarding the preparation and storage of cell-based MNs compared to conventional MNs. Specialized manufacturing techniques for cell-loaded MNs, such as pour molding and soaking cover, stepwise cryogenic micromoulding, microfluidics, and 3D printing, as well as electrospinning and electrospray, have demonstrated efficacy in maintaining cellular viability and long-term functionality within the MN microenvironment.¹³⁴ Keratinocytes (KCs) and fibroblasts (FBs), which play pivotal roles in immune regulation and tissue regeneration, are currently the only cell types approved by the U.S. Food and Drug Administration (FDA) for wound treatment applications. However, when they are introduced into a harsh wound microenvironment, their viability and biofunctions may be severely compromised, necessitating repeated doses.¹³⁵ To harness their therapeutic potential, a double-layer MN system was prepared by incorporating autologous KCs and FBs within biocompatible materials—gelatin-methacryloylchitosan (GelMA-CS), using the micromolding method. (Fig. 6(D)).⁷¹ The hydrogel-based cell scaffolds can provide mechanical support and stabilize the encapsulated cells, thereby enhancing their functional effectiveness. Furthermore, the chitosan scaffold confers antibacterial properties, improving cell viability and mitigating infection risk. The unique morphology of MNs substantially augments their specific surface area, thus facilitating the release of bioactive factors and providing sufficient contact with adjacent tissues. In diabetic mouse models, the system promotes the secretion of reparative cytokines such as TGF-α, TGF-β, and FGF, driving macrophage polarization toward an M2 phenotype, enhancing angiogenesis and collagen deposition, and facilitating full-thickness tissue regeneration. Overall, MNs offer a platform that not only enhances cell viability and activity at the wound site but also enables co-delivery of cells and bioactive agents, achieving sophisticated immune modulation and mimicking native skin regeneration in chronic wounds.

Beyond KCs and FBs, stem cell-based transplantation has emerged as a promising strategy for diabetic wound therapy. Among stem cell types, mesenchymal stem cells (MSCs) are particularly attractive due to their broad tissue availability (e.g., bone marrow, adipose tissue, umbilical cord, placenta, and peripheral blood), potent immunomodulatory capacity, secretion of pro-regenerative cytokines, and low immunogenicity.¹³⁶ While wound dressing patches based on stem cells have demonstrated promising potential in the treatment of diabetic wounds, their capabilities in maintaining cell stemness and facilitating effective cellular substance exchange under the harsh inflammatory microenvironment require further enhancement for clinical applications.^137,138 To address this, Wu et al. developed an innovative hydrogel-based microfluidic-engineered stem cell combinational platform for diabetic wound treatment, with MNs encapsulating ADSC spheroids (MN@SPs) (Fig. 6(E)).¹³⁹ By leveraging the precise fluid manipulation capabilities of the microfluidic template, stem cells are uniformly distributed into microwells on a specially designed microfluidic chip, enabling the in situ formation of stem cell spheroids (SPs) with a homogeneous morphology (approximately 154 μm). Then, HAMA pregel solutions can be injected into the template to encapsulate these SPs into MNs, where SPs demonstrate superior cellular viability, maintaining survival rates exceeding 70% for a period of 24 to 72 h. Additionally, the SPs within MN@SPs exhibit enhanced cellular functions and optimized cell–wound interactions, precisely delivering and exchanging multiple bioactive substances, which contribute to advanced neovascularization, collagen deposition, and tissue reconstruction. KEGG enrichment analysis reveals that SPs modulate immune responses by influencing Th1/Th2 differentiation, TNF signaling, and cytokine-mediated pathways. Despite these advances, additional investigations are necessary to comprehensively assess immune cell infiltration patterns and cytokine secretion dynamics.

4.5. Exosomes

Exosomes, a class of extracellular vesicles (EVs) secreted by almost every cell type,¹⁴⁰ serve as nano-carriers transporting bioactive substances including proteins, lipids, and nucleic acids (e.g., messenger RNAs, microRNAs, transfer RNAs, long noncoding RNAs, and DNA molecules) from donor to recipient cells.¹⁴¹ These vesicles protect their cargo from serum proteases and immune responses, thereby enhancing intercellular communication and modulating biological processes.^142,143 Most cell types—including immune, epithelial, endothelial, neuronal, and mesenchymal stem cells (MSCs)—release exosomes with therapeutic effects comparable to their source cells across all stages of diabetic wound healing.^144,145 They help regulate inflammation, promote re-epithelialization, stimulate angiogenesis, and facilitate ECM remodeling. Among these, MSC-derived exosomes (MSC-exos) exhibit regenerative and immunomodulatory functions akin to MSCs,¹⁴³ but without the associated risks of tumorigenesis, teratogenesis, or inconvenience in storage, transport, and dose control.¹⁴⁶ Owing to their high biocompatibility, low immunogenicity, stability, and scalable productivity, exosomes represent a safer, cell-free alternative with significant therapeutic potential for diabetic wound healing.¹⁴⁷ Integrating exosomes into MN platforms offers localized and sustained release, enhanced bioactivity, and a supportive healing microenvironment. These MN-based delivery systems prolong exosome retention, facilitate nutrient diffusion, and improve therapeutic outcomes.

As a representative example, Gan et al. developed a MN patch combining MSC-exos and antibacterial Ag nanoparticles (Ag-NPs) for diabetic wound healing (Fig. 7(A)).¹⁴⁸ The methacrylate gelatin (GelMA) hydrogel needle tips enable sustained, localized release of bioactive MSC-exos, while the adhesive silk fibroin methacryloyl (SilMA) hydrogel backing layer provides stable wound fixation and an antibacterial barrier. GelMA's microporous, biodegradable structure supports MSC-exos release over three days, facilitating uptake by endothelial cells and macrophages to promote angiogenesis and reduce inflammation. MSC-derived nanovesicles (MSC-NVs), produced by extruding MSCs through porous membranes,¹⁴⁹ offer a 250-fold higher yield and enhanced mRNA and protein expression compared to natural exosomes, underscoring their clinical potential.¹⁵⁰ Ferrum nanoparticle (Fe NP) treatment further improves the therapeutic cytokine profile of these nanovesicles (Fe-MSC-NVs) while limiting pro-inflammatory effects.⁸⁸ Building on this, a composite core–shell MN patch was designed, featuring an inner HA core encapsulating Fe-MSC-NVs for anti-inflammatory and angiogenic effects, and an outer HAMA shell loaded with polydopamine nanoparticles (PDA NPs) to counter ROS-induced oxidative stress (Fig. 7(B)).⁸⁸ In vitro and in vivo studies demonstrate that this system promotes macrophage polarization from the M1 to M2 phenotype, enhances anti-inflammatory cytokine secretion, suppresses pro-inflammatory mediators, reduces wound inflammation, and accelerates diabetic wound healing.

Fig. 7 Exosome delivery for immune regulation. (A) Schematic illustration of the healing mechanisms of the microneedles encapsulating MSC-derived exosomes (MSC-exos) for diabetic wounds, including sterilization, anti-inflammation, and angiogenesis. Reproduced from ref. 148 with permission from Elsevier, copyright 2022. (B) Schematic illustration of the structure of Fe-MSC-NVs/PDA microneedle patch, which encapsulating ferrum-mesenchymal stem cell-derived artificial nanovesicles (Fe-MSC-NVs) and polydopamine nanoparticles (PDA NPs), as well as the healing mechanisms of the wound closure process. Reproduced from ref. 88 with permission from John Wiley and Sons, copyright 2022. (C) Schematic illustration of the structure of the double-layer microneedle patch (MEs@PMN), encapsulating M2 macrophage-derived exosomes (MEs) in the needle tips and polydopamine (PDA) nanoparticles in the backing layer, as well as the mechanisms for treating diabetic wounds based on anti-inflammation and angiogenesis promotion. Reproduced from ref. 159 with permission from Elsevier, copyright 2023. (D) Schematic illustration of the mechanisms of the dissolvable microneedle patch (PLT-Exos@ADMMA-MN) on switching macrophage polarization, secreting inflammatory and angiogenic cytokines. Reproduced from ref. 162 with permission from Elsevier, copyright 2024.

Exosome functions are determined by their cellular origins, reflecting the properties of parent cells.¹⁵¹ Besides stem cell-derived exosomes, those derived from skin cells (e.g., keratinocytes,¹⁵² fibroblasts¹⁵³), immune cells (e.g., macrophages,¹⁵⁴ neutrophils¹⁵⁵) or body fluids (e.g., platelet-rich plasma¹⁵⁶) also show anti-inflammatory potential in diabetic wound healing. For instance, skin cell-derived exosomes modulate inflammation and promote skin regeneration, enhancing wound repair.¹⁵⁷ M2 macrophage-derived exosomes (MEs) promote macrophage switching from the pro-inflammatory M1 to anti-inflammatory M2 phenotype, accelerating healing.¹⁵⁸ Zeng et al. designed photosensitive MNs embedding MEs and PDA NPs (Fig. 7(C)).¹⁵⁹ The released MEs induce M2 polarization and reduce inflammation over 14 days, while PDA-mediated photothermal effects under 808 nm irradiation enhance angiogenesis and granulation, offering a promising diabetic wound therapy. Platelet-derived exosomes (PLT-Exos) also support tissue regeneration through angiogenesis, immunomodulation, and coagulation.^156,160 Platelets can be easily obtained, without complex cell culture protocols, thereby enabling scalable and safe exosome production.¹⁶¹ Cao et al. developed a methacrylated acellular dermal matrix MN patch (PLT-Exos@ADMMA-MN) for sustained PLT-Exos delivery (Fig. 7(D)).¹⁶² This system promotes M1-to-M2 macrophage transition, neovascularization, while inhibiting the secretion of pro-inflammatory cytokines by blocking the NOD-like receptor and Toll-like receptors.

4.6. Inorganic materials

Various metal ions, metal oxides, and inorganic particles have shown promise in modulating inflammation and immunity for diabetic wound healing.¹⁶³ Magnesium ions (Mg²⁺), essential cofactors for antioxidant enzymes, help alleviate oxidative stress, induce M2 macrophage polarization, and promote angiogenesis.^164,165 To this end, Wang et al. manufactured a poly (lactic-co-glycolic acid) (PLGA)-based MN patch loaded with magnesium hydride (MgH₂) macroparticles for defeating diabetic wounds (Fig. 8(A)).¹⁶⁶ Upon transdermal application, PLGA degradation generates acidic degradation byproducts (lactic acid and glycolic acid) that dissolve Mg(OH)₂, enabling sustained release of Mg²⁺ and hydrogen (H₂) for at least 7 days. These components collaboratively reduce ROS and enhance tissue regeneration by promoting M2 macrophage polarization, cell proliferation, and angiogenesis. Zinc ions (Zn²⁺), another key micronutrient, support immune regulation and tissue repair by mitigating oxidative stress and inflammation, promoting cell migration, angiogenesis and epithelial regeneration.^167,168 Yang et al. designed a hyaluronidase-responsive HA MN patch incorporating cerium/zinc-based nanomaterials for diabetic wound care (Fig. 8(B)).¹⁶⁹ This system offers dual functionality: antibacterial action via oxidative balance disruption and anti-inflammatory activity through controlled Zn²⁺ and Ce³⁺/Ce⁴⁺ redox release. RNA-seq analysis shows that the MN reprograms the NF-κB signaling pathway, reducing inflammation while enhancing proliferation and vascularization.

Fig. 8 Inorganic materials delivery for immune regulation. (A) Schematic illustration of a microneedle patch containing MgH₂ and its functional mechanisms for treating diabetic wounds. Reproduced from ref. 166 with permission from Elsevier, copyright 2023. (B) Schematic illustration of the fabrication of the hyaluronic acid (HA) microneedles embedded in a cerium/zinc-based nanomaterial (ZCO), as well as the mechanisms for synergistic diabetes wound healing by integrating bacterial eradication, anti-inflammatory and angiogenesis promotion. Reproduced from ref. 169 with permission from John Wiley and Sons, copyright 2023. (C) Schematic illustration of the anti-inflammation, angiogenesis, and cell proliferation mechanisms of microneedle therapy in diabetic wounds. Reproduced from ref. 173 with permission from John Wiley and Sons, copyright 2025. (D) Schematic illustration of the potential mechanisms of the Fe₃O₄/MXene heterojunction-laden double-layer biomolecular microneedles for the treatment of diabetic wounds, based on simultaneously up-regulating intercellular ROS and down-regulating extracellular ROS. Reproduced from ref. 174 with permission from John Wiley and Sons, copyright 2025. (E) Schematic illustration of the microneedle patch encapsulating the CuTA@MnO₂ nanoflake, which is synthesized by loading Cu²⁺ onto MnO₂ via in situ polymerization, with tannic acid (TA) as a linker, as well as the mechanisms for diabetic wound healing by integrating bacterial eradication, anti-inflammatory and angiogenesis promotion. Reproduced from ref. 93 with permission from Elsevier, copyright 2025.

Inorganic nanozymes, including cerium dioxide (CeO₂),^170–173 ferroferric oxide (Fe₃O₄),¹⁷⁴ Prussian blue (PB),^175,176 manganese dioxide (MnO₂),^93,177 etc., exhibit antioxidant and immunomodulatory properties in MN-based diabetic wound therapies.¹⁷⁸ Most typically, CeO₂ nanoparticles mitigate oxidative stress and exert anti-inflammatory effects via redox cycling between Ce³⁺ and Ce⁴⁺, mimicking SOD and CAT through surface oxygen vacancies.¹⁷⁹ Xuan et al. introduced the first example of amyloid-templated ceria nanozymes reinforced MNs, leveraging lysozyme amyloid fibrils (Lys-AFs) as templates to synthesize Lys-AFs-Ceria nanozymes (Fig. 8(C)).¹⁷³ These exhibit improved stability, a higher Ce³⁺/Ce⁴⁺ ratio, and enhanced catalytic activity. GOx is co-loaded via polyphenol-mediated interactions to enable glucose depletion. Lys-AFs-Ceria displays SOD-like activity at high Ce³⁺/Ce⁴⁺ ratios, converting O₂˙⁻ to H₂O₂ and O₂, and CAT-like activity as the ratio declines, further decomposing H₂O₂ to alleviate oxidative stress and hypoxia. The composite scaffold also promotes antibacterial effects and epithelial regeneration, while inducing M2 macrophage polarization to suppress inflammation. Similarly, Fe₃O₄ nanoparticles exhibit pH-sensitive SOD- and CAT-like activity.¹⁸⁰ You et al. synthesized a Fe₃O₄/MXene heterojunction integrated into GelMA MN tips (Fig. 8(D)).¹⁷⁴ The release of Fe²⁺/Fe³⁺ ions initiates nanozyme reactions and bacterial ferroptosis, thereby reducing extracellular ROS and increasing intracellular ROS, enhancing antioxidative and antimicrobial efficacy. The system promotes M2 macrophage recruitment, reduces inflammation, and accelerates collagen remodeling for diabetic wound healing. Prussian blue nanozymes (PBNs), nanoforms of PB, consist of a coordination network of the Fe²⁺–CN–Fe³⁺, exert therapeutic effects as multienzyme mimetics and inflammation inhibitors.¹⁸¹ Taking advantage of these properties, a SilMA MN patch encapsulating PBNs, VEGF, and polymyxin was fabricated to target the pathogenesis of diabetic wounds.¹⁷⁵ The released PBNs eliminate ROS-induced tissue damage and inflammatory responses by increasing antioxidant protein levels, improving mitochondrial functions, and attenuating apoptosis.

Metal ions can form stable complexes through bonding with functional groups of drug molecules such as natural polyphenols, which exhibit excellent biocompatibility and anti-inflammatory effects due to their free radical scavenging activity.¹⁸² These metal–polyphenol complexes support sustained drug release at wound sites while enhancing therapeutic efficacy. Accordingly, MNs integrated with metal ion complexes have emerged as promising immunomodulatory platforms for diabetic wound healing. Notable examples include metal–organic frameworks (MOFs) (e.g., magnesium organic frameworks (Mg-MOFs),^89,90 zeolitic imidazolate framework-8 (ZIF-8),⁹¹ etc.) and metal-phenolic nanosheets.^93,177 In this case, Andrabi et al. developed a hybrid-layered MN scaffold for sequential drug release across distinct healing phases.⁸⁹ The bottom layer delivers vancomycin, a W379 antimicrobial peptide, and a QK angiogenic peptide, while the top layer releases Mg-gallate MOFs that degrade in physiological fluids to release Mg²⁺ and GA. This design enables an initial antimicrobial burst followed by sustained delivery of agents promoting angiogenesis and M2 macrophage polarization, thereby reducing oxidative stress and accelerating tissue regeneration. Similarly, Yan et al. fabricated a photothermally controlled HAMA MN system encapsulating CuTA@MnO₂ nanoflakes—constructed by loading Cu²⁺ onto MnO₂ flakes, with TA as a linker (Fig. 8(E)).⁹³ MnO₂ nanoenzymes alleviate the inflammatory response via ROS neutralization and demonstrate antibacterial action in response to NIR illumination.⁵⁰ Upon NIR illumination, the MNs achieve rapid bacterial clearance through photothermal effects, followed by controlled decomposition of nanoflakes to release MnO₂ and TA for ROS scavenging. Released Cu²⁺ promotes vascularization and collagen remodeling. Transcriptomic analysis confirms downregulation of pro-inflammatory cytokines (e.g., TNF-α, IL-6, and IL-1β) and upregulation of pro-angiogenic and regenerative pathways, underscoring the potential of metal–polyphenol MNs in diabetic wound therapy.

Inorganic material-based MNs have shown promising anti-inflammatory effects and wound healing capabilities in diabetic wound treatment. Notably, metal materials such as Fe₃O₄ and PB have been approved by FDA for human use.^183,184 Nevertheless, in vivo and human experiments are still in the preliminary stage, facing several regulatory challenges and limiting the clinical outcomes. The long-term or massive use of metal ions may lead to metal poisoning, producing harmful ROS or even inactivating enzymes.¹⁸⁵ Additional investigations can be conducted to stabilize the release of metal ions, ensuring that therapeutic levels are achieved without causing toxicity to surrounding tissues, thereby endowing them with excellent translational prospects. This might involve the design of different combinations, structural optimization, and surface modification, as well as the development of coatings or encapsulation strategies.^186,187 Furthermore, long-term and comprehensive in vivo studies are urgently needed to better evaluate the systemic biodistribution, biosafety, biocompatibility and cumulative effects of these materials in biological systems, which would provide critical data that could pave the way for regulatory approval and subsequent clinical translation.¹⁷⁸

4.7. Gases

Gas therapy offers a “green” and biocompatible alternative for diabetic wound treatment, with exogenous gases demonstrating minimal cytotoxicity and drug resistance due to their role as endogenous signaling molecules.¹⁸⁸ Reductive gases, such as H₂, hydrogen sulfide (H₂S), carbon monoxide (CO), and nitric oxide (NO), exhibit potent anti-inflammatory effects and promote tissue regeneration. Among these, H₂ selectively neutralizes cytotoxic ROS, including hydroxyl radicals and peroxynitrites, thereby reducing oxidative stress, downregulating pro-inflammatory mediators, and promoting antioxidant enzyme expression.^189,190 Additionally, H₂ enhances fibroblast proliferation and endothelial differentiation, and displays anti-apoptotic effects, supporting wound repair.¹⁹¹ Tao et al. fabricated a composite MN patch for sustained, localized H₂ delivery.¹⁹² Ammonia borane (AB), a high-capacity H₂ donor, is encapsulated in mesoporous silica nanoparticles (MSN) to control hydrolysis. These AB@MSN particles are incorporated into PVP MNs, enabling direct tissue delivery and continuous H₂ release for 6 days. The released H₂ scavenges ROS, promotes M2 macrophage polarization, and triggers angiogenesis via growth factor secretion.

H₂S promotes diabetic wound healing by enhancing angiogenesis through upregulation of angiopoietin-1 and exerting anti-inflammatory effects via modulation of cytokine expression and M2 macrophage polarization, without notable side effects at physiological concentrations.^193,194 To harness these properties, Cai et al. developed H₂S-releasing MNs, embedding polymyxin B on CAT-templated nanozymes for sustained H₂S release.¹⁹⁵ These MNs scavenge excess ROS, promote M2 macrophage polarization, reduce inflammatory cytokines, and stimulate angiogenesis and nerve regeneration. Likewise, CO is known for its anti-inflammatory, antimicrobial, and regenerative functions.¹⁹⁶ Cao et al. constructed an ultrasound-responsive CO-releasing MN patch (MN@GOX@TiO_2−X@CO) that co-encapsulates a sonosensitizer (TiO_2−X), a ROS-responsive CO prodrug (MPA-CO), and GOx in a HA matrix (Fig. 9(A)).¹⁹⁷ Upon ultrasound activation, CO is locally released, reducing inflammatory cell infiltration, while concurrently inhibiting Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA) infection. The patch also promotes fibroblast migration and neovascularization, enhancing wound healing with minimal systemic toxicity.

Fig. 9 Gas delivery for immune regulation. (A) Schematic illustration of the synthetic process of the ultrasound-responsive CO-releasing microneedle patch (MN@GOX@TiO_2−X@CO), as well as the treatment of diabetic wounds by eradicating bacterial infection and accelerating wound repair through CO gas generation. Reproduced from ref. 197 with permission from John Wiley and Sons, copyright 2024. (B) Schematic illustration of the design of the microenvironment-responsive bilayer microneedles (G/AZ-MNs), and the mechanisms for promoting diabetic wound healing through glucose depletion and sustained release of NO. Reproduced from ref. 202 with permission from Elsevier, copyright 2024. (C) Schematic diagram of the synthesis and application of Chlorella-loaded poly(ionic liquid)-based microneedles (PILMN-Chl). PILMN-Chl could continuously supply sufficient oxygen through photosynthesis by the loaded Chlorella to the wound bed and exert sterilization activities by PIL to promote wound healing. Reproduced from ref. 205 with permission from John Wiley and Sons, copyright 2024. (D) Schematic illustration of the mechanisms of promoting diabetic wound healing via neurovascular immune modulation by multifunctional microneedles. Reproduced from ref. 206 with permission from Elsevier, copyright 2025.

NO, a signaling molecule synthesized from L-arginine by nitric oxide synthase (NOS), plays a crucial role in diabetic wound therapy by combating infection, regulating immune responses, promoting M2 macrophage polarization, and fostering angiogenesis.^198,199 Some NO-based systems have advanced to clinical trials for diabetic foot ulcer treatment.^200,201 Zeng et al. developed a cascade-responsive bilayer MN patch (G/AZ-MNs) featuring a degradable GOx-loaded tip and a base layer containing acid-sensitive Arg@ZIF-8 nanoparticles (Fig. 9(B)).²⁰² Upon application, MMP-9 triggers GOx release, catalyzing glucose into gluconic acid and H₂O₂. The resulting acidic environment degrades Arg@ZIF-8, releasing Zn²⁺ and Arg, which then reacts with H₂O₂ to produce NO continuously for up to 7 days, causing antibacterial effects and inducing macrophage polarization for anti-inflammation.

Diabetic wounds are characterized by chronic hypoxia due to impaired local blood flow, which suppresses cellular metabolism, inhibits fibroblast proliferation and angiogenesis, and aggravates inflammation and oxidative stress, collectively impeding wound healing.⁸ Traditional hypoxia-relief strategies, including hyperbaric oxygen therapy, are limited by poor tissue penetration and equipment complexity.¹⁸⁸ Algae-based O₂-generating MN systems have emerged as a promising alternative. Species of Cyanophyta²⁰³ and Chlorophyta^204,205 can photosynthesize O₂ sustainably under light exposure. For example, Gao et al. constructed Chlorella-loaded poly(ionic liquid) MNs (PILMN-Chl) capable of generating O₂ for over 30 hours (Fig. 9(C)).²⁰⁵ These MNs not only relieve local hypoxia but also reduce inflammation and bacterial load, thereby accelerating wound closure and promoting angiogenesis.

Combined gas therapies offer synergistic benefits. For instance, NO and O₂ can jointly regulate neurovascular remodeling and immune responses. Liu et al. designed a dual-layer MN patch that releases NO and O₂ sequentially—the inner layer contains a NO donor, while the outer MnO₂ layer scavenges ROS and generates O₂, connected via phenylborate esters (Fig. 9(D)).²⁰⁶ This system promotes M2 macrophage polarization, neurovascular regeneration, and improves diabetic wound healing. However, challenges remain, for the potential interaction between NO and O₂ to form toxic nitrogen dioxide (NO₂), highlighting the need for optimized delivery timing or compartmentalization strategies.²⁰⁷

4.8. Integrated platforms

Recent developments in immunomodulatory MNs for diabetic wound healing have progressed beyond simple release of anti-inflammatory agents, incorporating physical stimuli such as electrical, light, and thermal-based cues to enhance therapeutic efficacy.

Exogenous electrical stimulation (ES) has shown potential to regulate cellular behaviors including cell proliferation and migration, immune modulation, angiogenesis and collagen deposition.²⁰⁸ Despite clinical benefits of traditional ES devices, their dependence on external power supplies, limited portability, and poor mechanical compatibility with tissues hinder long-term application and patient compliance.²⁰⁹ Triboelectric nanogenerators (TENGs), which convert biomechanical motion into electrical energy, offer a promising alternative due to their flexibility, wearability, low cost, and biocompatibility.^94,210 A self-powered MN system (TZ@mMN-TENG) was developed by integrating MNs loaded with tannin@ZnO microparticles (TZ@mMN) and TENG technology.⁹⁴ The system delivers tannin and Zn²⁺ to eliminate ROS and bacteria, while polyaniline (PANI) doping imparts electrical conductivity. The TENG captures mechanical energy to power localized ES through the MNs, reducing inflammatory markers (TNF-α, IL-6) and enhancing angiogenic factors (CD31, VEGF), thereby accelerating diabetic wound healing. This approach demonstrates the synergistic potential of combining bioactive materials and self-powered ES in advanced wound care platforms. However, the TZ@mMN-TENG relies on external mechanical energy to activate electric fields, with output stability constrained by patient mobility and unverified long-term biocompatibility of triboelectric materials. To address these limitations, enzymatic biofuel cells (BFCs) have emerged as promising self-powered alternatives. BFCs use biological enzymes as efficient electrocatalysts to convert endogenous substrates such as glucose and lactic acid into continuous, stable electrical currents.²¹¹ Therefore, Zhang et al. fabricated a self-powered MN patch by integrating MN arrays with a BFC system consisting of conductive anode and cathode arrays containing GOx and horseradish peroxidase (HRP) encapsulated in ZIF-8 nanoparticles (Fig. 10(A)).²¹² The GOx-HRP cascade reduces local hyperglycemia and generates a sustained microcurrent. Immunohistochemical analysis reveals significant downregulation of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) and upregulation of anti-inflammatory markers (IL-4, IL-13), attributed to both glucose depletion and bioelectric stimulation via the NOS pathway.

Fig. 10 Integrated platforms for synergistic immune regulation. (A) Schematic diagram of the enzyme cascade reaction generated by the self-powered enzyme-linked microneedle patch, as well as the mechanisms for accelerating diabetic wound healing. Reproduced from ref. 212 with permission from The American Association for the Advancement of Science, copyright 2023. (B) Schematic illustration of the mechanisms by which the photosensitizer-loaded microneedle patch enhances diabetic wound healing through photodynamic therapy to eradicate biofilms. Reproduced from ref. 216 with permission from John Wiley and Sons, copyright 2025. (C) Schematic diagram of the mechanisms of the double-layer microneedle patch (PH/CuS/TM MNs) for treating diabetic wounds, via eradicating bacteria, scavenging ROS and immunomodulation while promoting angiogenesis, enabling programmed treatment of diabetic wounds. Reproduced from ref. 95 with permission from American Chemical Society, copyright 2024. (D) Schematic illustration of the preparation of the NIR-responsive composited microneedles loaded with photothermal conjugated polymer nanoparticles and basic fibroblast growth factor (FGF-2), as well as the three major mechanisms by which composited microneedles promote diabetic wound healing by destroying bacterial biofilms, reducing the level of ROS and promoting angiogenesis. Reproduced from ref. 217 with permission from American Chemical Society, copyright 2025.

Electroacupuncture stimulates specific acupoints to regulate systemic inflammation through neural activation.²¹³ Hou et al. combined electroacupuncture at the Dazhui acupoint (GV14) with polyphenol-mediated conductive hydrogel MNs.²¹⁴ Polydopamine-modified poly(3,4-ethylenedioxythiophene) (PPEDOT) nanoparticles confer conductivity to the MNs, enabling electroacupuncture-triggered local modulation. This approach suppresses inflammation by inhibiting the p38MAPK pathway and promoting M2 macrophage polarization, thereby enhancing anti-inflammatory cytokine expression, facilitating nerve regeneration, and accelerating tissue repair.

Photodynamic therapy (PDT) has emerged as a promising strategy for treating bacterial infections associated with diabetic wounds.²¹⁵ PDT employs photosensitizers to generate ROS upon light irradiation, which induces damage to bacterial cell wall, proteins, nucleic acids, and other cellular components, leading to antimicrobial and anti-biofilm effects. To enhance the specificity and efficacy of PDT in multidrug-resistant infections, Xie et al. designed a dissolvable MN patch incorporating benzoxaborole-functionalized photosensitizers (TPI-BOB) for targeted, localized PDT (Fig. 10(B)).²¹⁶ This MN system enables rapid and site-specific delivery of TPI-BOB into bacterial biofilms to effectively disrupt biofilm integrity and eradicate pathogenic bacteria. In addition to its antibacterial effects, the treatment significantly reduces local inflammation and promotes tissue repair by enhancing collagen deposition and angiogenesis, thereby accelerating wound regeneration.

Photothermal therapy (PTT) is an effective adjunct to immunomodulatory MNs for diabetic wound treatment. Unlike PDT, which relies on cytotoxic ROS, PTT employs NIR light to generate localized heat that inhibits bacteria, reduces inflammation, and promotes healing.^218,219 Guo et al. constructed a double-layer MN patch (PH/CuS/TM MNs) wherein the MN tips release TA and Eu³⁺ from TM nanoparticles under the wound's acidic environment to scavenge ROS and enhance angiogenesis (Fig. 10(C)).⁹⁵ CuS nanoparticles in the base act as photothermal agents activated by 808 nm NIR light, effectively eradicating bacteria. This combination reduces inflammatory cytokines and polarizes macrophages toward the anti-inflammatory M2 phenotype. Wang et al. prepared photothermal-responsive MNs loaded with minocycline-encapsulated conjugated polymer nanoparticles and bFGF (Fig. 10(D)).²¹⁷ NIR irradiation triggers minocycline release, eliminating biofilms and drug-resistant bacteria. The synergistic photothermal, antimicrobial, and regenerative effects reduce oxidative stress and inflammatory markers. Zhu et al. fabricated a hydrogel MN patch containing taurine-loaded Prussian blue nanoparticles (Taurine@PB) for diabetic wounds.¹⁷⁶ The acidic microenvironment and mild photothermal stimulation promote taurine release, activating macrophage efferocytosis and clearing senescent cells. This treatment shifts immune cells to anti-inflammatory phenotypes, inhibits neutrophil extracellular traps, and decreases pro-inflammatory cytokines. Transcriptomic analysis reveals the mechanism involves regulation of the ROS/NF-κB/Sirt3 pathway.

Despite the significant potential demonstrated by these combined therapies in theoretical and laboratory studies, the clinical implementation of physical stimulation MN devices continues to face several substantial challenges. The cost-effectiveness and manufacturing challenges associated with high-performance biomaterials or sophisticated equipment remain unresolved, as the high production expenses of advanced MN platforms may impose an economic burden on end-users, consequently restricting their feasibility for broad clinical adoption.²²⁰ Moreover, MNs triggered by external physical stimuli necessitate an external energy source, such as laser irradiation. Portable units for administering these external stimuli may not be readily available, potentially presenting not only financial barriers for patients but also practical difficulties in self-administration. Hence, these integrated MN platforms are more suited for hospital-based applications rather than home use by patients.²²¹

5. Conclusions and perspectives

Diabetic wounds are characterized by excessive inflammatory responses and an abnormal immune microenvironment, driven by hyperglycemia, bacterial infections, impaired angiogenesis, and disrupted neurogenesis at the wound site. MN patches offer a minimally invasive and efficient strategy for localized delivery of therapeutic agents directly to the wound, enhancing patient compliance while bypassing systemic circulation to reduce side effects. This approach represents a promising innovation for accelerating wound healing. Immunomodulatory MNs provide spatially precise delivery of encapsulated anti-inflammatory bioactive substances, ensuring targeted tissue interaction and sustained therapeutic activity. This review highlights key design considerations for immunomodulatory MNs in diabetic wound healing, focusing on materials, structural design, and therapeutic payloads. These elements are tailored to address the unique features of diabetic wound immune microenvironments, including dysfunctional immune cell infiltration, persistent cytokine activation, excessive metabolic by-products, and elevated ROS. Regarding materials, immunomodulatory MNs incorporate anti-inflammatory substrates to rebalance the disrupted immune landscape. Structurally, the primary design principles include safe skin penetration, minimal pain, enhanced patient adherence, and efficient drug delivery. Geometric parameters and needle shape critically influence penetration efficacy, adhesion, and payload release, making their optimization essential for maximizing immunomodulatory drug performance and therapeutic outcomes. For therapeutic delivery, immunomodulatory MNs enable precise dosage control and localized release of diverse bioactive agents, including small molecules, proteins, nucleic acids, cells, exosomes, inorganic materials, and gases. This platform supports the development of differential release systems, facilitating multidrug combination therapies to enhance anti-inflammatory effects. Moreover, integrating MNs with adjunct therapies such as electrotherapy or phototherapy can yield synergistic effects that cooperatively promote wound healing. The combination of MN-based drug delivery with complementary therapeutic modalities creates a favorable microenvironment to modulate dysregulated inflammation in diabetic wounds, offering significant potential for tissue regeneration and improved clinical outcomes.

Despite significant advancements in the development of immunomodulatory MNs for diabetic wound healing, the field still faces considerable challenges in future clinical applications. One key limitation lies in the poor concordance rate in preclinical models for diabetic wound studies. A variety of animal models utilized for in vivo experiments may demonstrate different physiology and healing mechanisms across different species, thereby hindering meaningful comparisons between research outcomes. Generally employed murine or rodent-based models for diabetic wound healing inadequately replicate human wound conditions due to their propensity to contract instead of re-epithelialize. As such, encouraging results from current murine studies may not be readily translated into clinical practice for people with diabetes management. To enhance the accuracy and reliability of experimental outcomes and better validate potential clinical applications, it is preferable to employ animal models that more closely approximate human physiological conditions, such as larger mammals like pigs or monkeys. In parallel, the convergence of innovative experimental methodologies, such as organs-on-chips technology, may represent a promising direction for the verification of in vivo assays. The second major challenge pertains to safety considerations surrounding immunomodulatory MNs, given their potential to excessively suppress immune responses, which may inadvertently precipitate immune-related diseases and cancers. Consequently, there exists a pressing need for immunomodulatory MNs exhibiting precise targeting capabilities to proactively circumvent unintended health complications. Moreover, existing studies have achieved advancements in improving biocompatibility and demonstrating initial safety profiles through in vitro short-term blood compatibility and cytotoxicity to different fibroblasts and keratinocytes, leaving a paucity of data concerning the longevity of therapeutic benefits and potential delayed-onset adverse effects. Although materials employed for MN manufacture are typically biodegradable into harmless metabolites, systematic evaluation is warranted to determine whether repeated administration frequency impacts normal cutaneous function and whether residual material deposition elicits undesirable immunogenic responses. Therefore, comprehensive long-term biocompatibility and safety assessments are urgently needed to thoroughly examine the sustained safety profile and therapeutic effectiveness of immunomodulatory MNs in treating diabetic wounds, thereby facilitating their transition into widespread clinical adoption. Thirdly, individual patient differences and complex wound environments result in the variability in wound characteristics and healing needs among diabetic patients, causing different treatment efficacy and adversely impacting the successful application of MNs. The development of personalized wound care MNs could provide precisely tailored treatments according to individual wound profiles, contributing to more compatible, more effective, and patient-specific wound management. Furthermore, the engineering processes of preparing MNs capable of integrating multiple therapeutic agents often involve sophisticated manufacturing techniques, which contribute to high production costs and technical barriers. The development of straightforward, scalable, and cost-effective fabrication methods would increase their clinical application in managing chronic wounds. Equally important are the establishment of clear regulatory guidelines and stringent safety protocols to govern the design, production, and clinical implementation of these devices.

In future, significant advancements in comprehending and regulating both the onset and resolution of inflammatory processes are essential for improving diabetic wound healing. While current immunomodulatory MNs have shown promise in regulating microenvironment factors, such as macrophages, pro-inflammatory cytokines, and ROS, the underlying molecular mechanisms of these inflammation-targeted strategies remain insufficiently characterized due to the complexity of the diabetic milieu. Further in vitro and in vivo experiments are therefore necessary to validate their efficacy and elucidate mechanistic pathways. Meanwhile, emerging strategies that target alternative immune cell populations (e.g., NK cells, DCs, and T cells) or metabolic by-products (e.g., AGEs, MMPs) represent promising avenues for future MN-based immunotherapies. Moreover, the simultaneous and/or gradient administration of several different immunomodulatory agents using MNs offers an intriguing strategy for multi-target interventions in chronic wound management. Consequently, these directions open numerous opportunities to identify novel biological targets and develop potent anti-inflammatory therapeutics, thereby paving the way for more comprehensive and effective MN treatment modalities.

Immunomodulatory MNs construct a biosafe therapeutic delivery platform with precisely controlled and sustained release characteristics, demonstrating significant translational potential for clinical applications in diabetic wound management. However, the molecular-level mechanisms underlying the interactions between many therapeutic agents and the inflammatory microenvironment remain unclear, warranting thorough investigations to elucidate the therapeutic roles of various agents in wound healing processes, thereby mitigating risks and enhancing the therapeutic profile. Notably, both the physiological concentrations of specific immunomodulatory molecules and the ideal concentration ratios in combination therapies demand rigorous regulation of safe dosage parameters to maximize therapeutic benefits while preventing cytotoxic consequences. Moreover, enhancing drug-loading capacity remains a critical goal. Strategies such as increasing the MN length, enlarging the patch area, or employing carrier polymer-free dissolvable MNs show promise in significantly boosting drug payloads. Intensive research in bioengineering methodologies, particularly involving cells and exosomes, has demonstrated that these biological components can be effectively modified through advanced strategies such as physical, chemical, or biological preconditioning techniques as well as genetic engineering approaches. These bioengineered immunomodulatory MNs not only enhance bioactivity but also offer inspiring therapeutic avenues for improved immunomodulation and diabetic wound management. Given the remarkable advancements in flexible electronics and wearable smart biomedical devices, the integration of MN platforms with intelligent, environment-responsive materials offers potential functionalities including real-time wound monitoring and diagnostic capabilities, along with dynamic modulation of inflammatory responses. This approach presents considerable potential for applications in chronic wound management and real-time wound assessment.

Author contributions

Conceptualization, Shenqiang Wang; supervision, Shenqiang Wang; and writing – review and editing, Yixuan Han, Shengjie Ge, Hejiao Yin, Dazhong Han, and Shenqiang Wang. All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

No primary research results, software or code have been included and no new data were generated or analyzed as part of this review.

Acknowledgements

This research was funded by the Leading Talents of Innovation and Entrepreneurship in Gusu District (ZXL2024366), the Natural Science Foundation of China (32471380), and the Startup Packages of Soochow University.

References

1. H. Sun, P. Saeedi, S. Karuranga, M. Pinkepank, K. Ogurtsova, B. B. Duncan, C. Stein, A. Basit, J. C. N. Chan, J. C. Mbanya, M. E. Pavkov, A. Ramachandaran, S. H. Wild, S. James, W. H. Herman, P. Zhang, C. Bommer, S. Kuo, E. J. Boyko and D. J. Magliano, Diabetes Res. Clin. Pract., 2022, 183, 109119.
2. D. G. Armstrong, T.-W. Tan, A. J. M. Boulton and S. A. Bus, JAMA, 2023, 330, 62–75.
3. G. Akkus and M. Sert, World J. Diabetes, 2022, 13, 1106–1121.
4. O. A. Peña and P. Martin, Nat. Rev. Mol. Cell Biol., 2024, 25, 599–616.
5. S. Singh, A. Young and C.-E. McNaught, Surgery, 2017, 35, 473–477.
6. X. Ren, Z. Hou, B. Pang, C. Gao and R. Tang, Adv. Healthcare Mater., 2024, 13, 2302287.
7. S. Darvishi, S. Tavakoli, M. Kharaziha, H. H. Girault, C. F. Kaminski and I. Mela, Angew. Chem., Int. Ed., 2022, 61, e202112218.
8. J. Huang, R. Yang, J. Jiao, Z. Li, P. Wang, Y. Liu, S. Li, C. Chen, Z. Li, G. Qu, K. Chen, X. Wu, B. Chi and J. Ren, Nat. Commun., 2023, 14, 7856.
9. G. Li, C.-N. Ko, D. Li, C. Yang, W. Wang, G.-J. Yang, C. Di Primo, V. K. W. Wong, Y. Xiang, L. Lin, D.-L. Ma and C.-H. Leung, Nat. Commun., 2021, 12, 3363.
10. G. Sloan, D. Selvarajah and S. Tesfaye, Nat. Rev. Endocrinol., 2021, 17, 400–420.
11. Y.-Z. Lu, B. Nayer, S. K. Singh, Y. K. Alshoubaki, E. Yuan, A. J. Park, K. Maruyama, S. Akira and M. M. Martino, Nature, 2024, 628, 604–611.
12. Y.-Y. Huang, C.-W. Lin, N.-C. Cheng, S. M. Cazzell, H.-H. Chen, K.-F. Huang, K.-Y. Tung, H.-L. Huang, P.-Y. Lin, C.-K. Perng, B. Shi, C. Liu, Y. Ma, Y. Cao, Y. Li, Y. Xue, L. Yan, Q. Li, G. Ning and S.-C. Chang, JAMA Netw. Open, 2021, 4, e212260.
13. P. Jiang, Q. Li, Y. Luo, F. Luo, Q. Che, Z. Lu, S. Yang, Y. Yang, X. Chen and Y. Cai, Front. Endocrinol., 2023, 14, 1221705.
14. M. Farahani and A. Shafiee, Adv. Healthcare Mater., 2021, 10, 2100477.
15. R. Jamaledin, C. K. Y. Yiu, E. N. Zare, L.-N. Niu, R. Vecchione, G. Chen, Z. Gu, F. R. Tay and P. Makvandi, Adv. Mater., 2020, 32, 2002129.
16. M. Kharaziha, A. Baidya and N. Annabi, Adv. Mater., 2021, 33, 2100176.
17. H. Cho, M. R. Blatchley, E. J. Duh and S. Gerecht, Adv. Drug Delivery Rev., 2019, 146, 267–288.
18. V. Papayannopoulos, Nat. Rev. Immunol., 2018, 18, 134–147.
19. S. L. Wong, M. Demers, K. Martinod, M. Gallant, Y. Wang, A. B. Goldfine, C. R. Kahn and D. D. Wagner, Nat. Med., 2015, 21, 815–819.
20. K. Mukai, M. Tsai, H. Saito and S. J. Galli, Immunol. Rev., 2018, 282, 121–150.
21. A. Tellechea, E. C. Leal, A. Kafanas, M. E. Auster, S. Kuchibhotla, Y. Ostrovsky, F. Tecilazich, D. Baltzis, Y. Zheng, E. Carvalho, J. M. Zabolotny, Z. Weng, A. Petra, A. Patel, S. Panagiotidou, L. Pradhan-Nabzdyk, T. C. Theoharides and A. Veves, Diabetes, 2016, 65, 2006–2019.
22. P. K. Barman, N. Urao and T. J. Koh, J. Pathol., 2019, 249, 435–446.
23. C. Chen, T. Liu, Y. Tang, G. Luo, G. Liang and W. He, Burns Trauma, 2023, 11, tkac057.
24. A. E. Boniakowski, A. S. Kimball, B. N. Jacobs, S. L. Kunkel and K. A. Gallagher, J. Immunol., 2017, 199, 17–24.
25. S. Chen, R. Li, C. Cheng, J.-Y. Xu, C. Jin, F. Gao, J. Wang, J. Zhang, J. Zhang, H. Wang, L. Lu, G.-T. Xu and H. Tian, Cell Biol. Int., 2018, 42, 877–889.
26. J. Cavalcante-Silva and T. J. Koh, J. Immunol., 2023, 210, 981–990.
27. J. Cavalcante-Silva and T. J. Koh, J. Leukocyte Biol., 2025, 117, qiaf044.
28. M. Cabeza-Cabrerizo, A. Cardoso, C. M. Minutti, M. Pereira da Costa and C. Reis e Sousa, Annu. Rev. Immunol., 2021, 39, 131–166.
29. C. O. Audu, S. Wolf, W. Melvin, F. Davis, S. Sharma, K. Mangum, E. Barrett, A. Joshi, A. T. Obi and K. A. Gallagher, Arterioscler., Thromb., Vasc. Biol., 2022, 42, A326–A326.
30. S. Maschalidi, P. Mehrotra, B. N. Keçeli, H. K. L. De Cleene, K. Lecomte, R. Van der Cruyssen, P. Janssen, J. Pinney, G. van Loo, D. Elewaut, A. Massie, E. Hoste and K. S. Ravichandran, Nature, 2022, 606, 776–784.
31. Z. Wang, F. Qi, H. Luo, G. Xu and D. Wang, Front. Immunol., 2022, 13, 789274.
32. X. Xue and D. M. Falcon, Int. J. Mol. Sci., 2019, 20, 6097.
33. M. Qu, W. Xu, X. Zhou, F. Tang, Q. Chen, X. Zhang, X. Bai, Z. Li, X. Jiang and Q. Chen, Adv. Funct. Mater., 2024, 34, 2314500.
34. M. Rodrigues, N. Kosaric, C. A. Bonham and G. C. Gurtner, Physiol. Rev., 2019, 99, 665–706.
35. A. E. Louiselle, S. M. Niemiec, C. Zgheib and K. W. Liechty, Transl. Res., 2021, 236, 109–116.
36. D. Liu, P. Yang, M. Gao, T. Yu, Y. Shi, M. Zhang, M. Yao, Y. Liu and X. Zhang, Clin. Sci., 2019, 133, 565–582.
37. X. Zheng, S. Narayanan, V. G. Sunkari, S. Eliasson, I. R. Botusan, J. Grünler, A. I. Catrina, F. Radtke, C. Xu, A. Zhao, N. R. Ekberg, U. Lendahl and S.-B. Catrina, Proc. Natl. Acad. Sci. U. S. A., 2019, 116, 6985–6994.
38. Y. Yang, S. Huang, Q. Ma, N. Li, R. Li, Y. Wang and H. Liu, Regener. Biomater., 2024, 11, rbae062.
39. M. Khalid, G. Petroianu and A. Adem, Biomolecules, 2022, 12, 542.
40. M. Hesketh, K. B. Sahin, Z. E. West and R. Z. Murray, Int. J. Mol. Sci., 2017, 18, 1545.
41. H. Hu, H. Jiang, H. Ren, X. Hu, X. Wang and C. Han, Diabetes/Metab. Res. Rev., 2015, 31, 127–137.
42. N. López-López, I. González-Curiel, M. B. Treviño-Santa Cruz, B. Rivas-Santiago, V. Trujillo-Paez, J. A. Enciso-Moreno and C. J. Serrano, Arch. Dermatol. Res., 2014, 306, 809–821.
43. J. Lang, C. Yang, L. Liu, L. Li, L. Wu, Y. Liu, H. Luo, L. Yan, S. Chen, J. Ning and C. Yang, Exp. Cell Res., 2021, 403, 112550.
44. J. B. Acosta, D. G. del Barco, D. C. Vera, W. Savigne, P. Lopez-Saura, G. G. Nieto and G. S. Schultz, Int. Wound J., 2008, 5, 530–539.
45. L. Sorokin, Nat. Rev. Immunol., 2010, 10, 712–723.
46. K. Rassek, K. Iżykowska, M. Żurawek, M. Pieniawska, K. Nowicka, X. Zhao and G. K. Przybylski, Int. J. Mol. Sci., 2023, 24, 3531.
47. Q. Yu, Z. Zheng, H. Zhang, E. Xie, L. Chen, Z. Jiang, Y. Gao, J. Ma and L. Yang, Interdiscip. Med., 2025, 3, e20240062.
48. S. Polaka, P. Katare, B. Pawar, N. Vasdev, T. Gupta, K. Rajpoot, P. Sengupta and R. K. Tekade, ACS Omega, 2022, 7, 30657–30672.
49. F. Giacco, M. Brownlee and A. M. Schmidt, Circ. Res., 2010, 107, 1058–1070.
50. S. Wang, H. Zheng, L. Zhou, F. Cheng, Z. Liu, H. Zhang, L. Wang and Q. Zhang, Nano Lett., 2020, 20, 5149–5158.
51. B. D'Autréaux and M. B. Toledano, Nat. Rev. Mol. Cell Biol., 2007, 8, 813–824.
52. G. Jiang, T. Jiang, J. Chen, H. Yao, R. Mao, X. Yang, Z. Chen and W. Li, J. Biochem. Mol. Toxicol., 2023, 37, e23407.
53. Y. Qian, J. Ding, R. Zhao, Y. Song, J. Yoo, H. Moon, S. Koo, J. S. Kim and J. Shen, Chem. Soc. Rev., 2025, 54, 33–61.
54. Y.-H. Chiu, Y.-W. Wu, J.-I. Hung and M.-C. Chen, Acta Biomater., 2021, 130, 223–233.
55. Y. Gan, B. Liang, Y. Gong, L. Wu, P. Li, C. Gong, P. Wang, Z. Yu, L. Sheng, D.-P. Yang and X. Wang, Chem. Eng. J., 2024, 481, 148592.
56. J. Wang, H. Liu, X. Shi, S. Qin, J. Liu, Q. Lv, J. Liu, Q. S. Li, Z. Wang and L. Wang, Adv. Mater., 2024, 36, 2311593.
57. H. Liu, S. Qin, H. Zhang, Z. Chen, Y. Zhao, J. Liu, Y. Deng, M. Liu, W. Chen, Z. Wang and L. Wang, Adv. Funct. Mater., 2025, 35, 2404461.
58. J. Mao, Z. Cai, Z. Liu, S. Qian, B. Zhao, Y. Zhang, Y. Zhuang, L. Zhang, X. Mao, Y. Zhang, W. Cui and X. Sun, Chem. Eng. J., 2022, 450, 137880.
59. G. Li, Y. Jiang, M. Li, W. Zhang, Q. Li and K. Tang, Int. J. Biol. Macromol., 2021, 168, 233–241.
60. Q. Zong, X. Peng, H. Wu, Y. Ding, X. Ye, X. Gao, W. Sun and Y. Zhai, Int. J. Biol. Macromol., 2024, 257, 128581.
61. N. Lohmann, L. Schirmer, P. Atallah, E. Wandel, R. A. Ferrer, C. Werner, J. C. Simon, S. Franz and U. Freudenberg, Sci. Transl. Med., 2017, 9, eaai9044.
62. Z. Le, Y. Shou, R. R. Li, L. Liu, R. Tan, C. J. Charles, Z. Liu, Y. Chen and A. Tay, Adv. Funct. Mater., 2024, 34, 2402539.
63. Y. Zhang, S. Wang, Y. Yang, S. Zhao, J. You, J. Wang, J. Cai, H. Wang, J. Wang, W. Zhang, J. Yu, C. Han, Y. Zhang and Z. Gu, Nat. Commun., 2023, 14, 3431.
64. X. Li, Z. Sun, X. Shang, L. Chen, X. Shi, W. Xu, S. Fu, Q. He, Q. Liang, J. Ma, X. Sun, J. Lu and W. Jin, Mater. Today Bio, 2024, 29, 101374.
65. C.-H. Kuan, L. Chang, C.-Y. Ho, C.-H. Tsai, Y.-C. Liu, W.-Y. Huang, Y.-N. Wang, W.-H. Wang and T.-W. Wang, Biomaterials, 2025, 314, 122848.
66. M. Zheng, T. Sheng, J. Yu, Z. Gu and C. Xu, Nat. Rev. Bioeng., 2024, 2, 324–342.
67. G. Yan, K. S. Warner, J. Zhang, S. Sharma and B. K. Gale, Int. J. Pharm., 2010, 391, 7–12.
68. H. Roh, Y. J. Yoon, J. S. Park, D.-H. Kang, S. M. Kwak, B. C. Lee and M. Im, Nano-Micro Lett., 2021, 14, 24.
69. L. K. Vora, I. A. Tekko, F. V. Zanutto, A. Sabri, R. K. M. Choy, J. Mistilis, P. Kwarteng, C. Jarrahian, H. O. McCarthy and R. F. Donnelly, Pharmaceutics, 2024, 16, 142.
70. Q. Zhang, L. Shi, H. He, X. Liu, Y. Huang, D. Xu, M. Yao, N. Zhang, Y. Guo, Y. Lu, H. Li, J. Zhou, J. Tan, M. Xing and G. Luo, ACS Nano, 2022, 16, 10163–10178.
71. X. Huang, X. Niu, Y. Ma, X. Wang, T. Su, Y. He, F. Lu, J. Gao and Q. Chang, J. Adv. Res., 2024, 66, 237–249.
72. D. Han, R. S. Morde, S. Mariani, A. A. La Mattina, E. Vignali, C. Yang, G. Barillaro and H. Lee, Adv. Funct. Mater., 2020, 30, 1909197.
73. Y. Ren, K. Yang, Z. Wang, Z. Zhang, Y. Chen, X. Shi, J. Zhang, Y. Chen, D. Huang, J. Li and Z. Li, J. Controlled Release, 2024, 368, 199–207.
74. N. Bandara and J. Wu, ACS Sustainable Chem. Eng., 2018, 6, 1152–1161.
75. B. Ciui, A. Martin, R. K. Mishra, B. Brunetti, T. Nakagawa, T. J. Dawkins, M. Lyu, C. Cristea, R. Sandulescu and J. Wang, Adv. Healthcare Mater., 2018, 7, 1701264.
76. X. Zhang, G. Chen, L. Sun, F. Ye, X. Shen and Y. Zhao, Chem. Eng. J., 2021, 406, 126741.
77. M. Guo, Y. Wang, B. Gao and B. He, ACS Nano, 2021, 15, 15316–15327.
78. Z. Zhu, J. Wang, X. Pei, J. Chen, X. Wei, Y. Liu, P. Xia, Q. Wan, Z. Gu and Y. He, Sci. Adv., 2023, 9, eadh2213.
79. P. Makvandi, A. Maleki, M. Shabani, A. R. J. Hutton, M. Kirkby, R. Jamaledin, T. Fang, J. He, J. Lee, B. Mazzolai, R. F. Donnelly, F. R. Tay, G. Chen and V. Mattoli, Matter, 2022, 5, 390–429.
80. X. Wei, Y. Wang, Y. Liu, K. Ji, K. Li, J. Wang and Z. Gu, Matter, 2024, 7, 826–854.
81. T. Liu, Y. Sun, G. Jiang, W. Zhang, R. Wang, L. Nie, A. Shavandi, K. E. Yunusov, U. E. Aharodnikau and S. O. Solomevich, Acta Biomater., 2023, 160, 32–44.
82. L. Zhou, Z. Zeng, J. Liu, F. Zhang, X. Bian, Z. Luo, H. Du, P. Zhang and Y. Wen, Adv. Funct. Mater., 2024, 34, 2312499.
83. Y. Wang, P. Guan, R. Tan, Z. Shi, Q. Li, B. Lu, E. Hu, W. Ding, W. Wang, B. Cheng, G. Lan and F. Lu, Adv. Fiber Mater., 2024, 6, 1596–1615.
84. R. E. Tao, S. Prajapati, J. N. Pixley, A. Grada and S. R. Feldman, Antibiotics, 2023, 12, 1152.
85. W. Liu, X. Zhai, X. Zhao, Y. Cai, X. Zhang, K. Xu, J. Weng, J. Li and X. Chen, Adv. Healthcare Mater., 2023, 12, 2300297.
86. N. Yahfoufi, N. Alsadi, M. Jambi and C. Matar, Nutrients, 2018, 10, 1618.
87. J. Ran, Z. Xie, L. Yan, C. Ye, Y. Hou, Y. Hu, X. Lu and C. Xie, Small, 2024, 20, 2404538.
88. W. Ma, X. Zhang, Y. Liu, L. Fan, J. Gan, W. Liu, Y. Zhao and L. Sun, Adv. Sci., 2022, 9, 2103317.
89. S. M. Andrabi, S. M. S. Shahriar, Y. Tian, F. Hayati, Y. Su, F. Zhang, N. S. Sharma, G. Wang, S. L. Wong, Z. Yan, G. Huang and J. Xie, Adv. Funct. Mater., 2025, 35, 2422150.
90. M. Yin, J. Wu, M. Deng, P. Wang, G. Ji, M. Wang, C. Zhou, N. T. Blum, W. Zhang, H. Shi, N. Jia, X. Wang and P. Huang, ACS Nano, 2021, 15, 17842–17853.
91. W. Li, X. Tan, Y. Liang, N. Chen, D. Feng, Y. Tao, T. Liu, X. Wu, H. Lu, L. Liu, F. Feng and L. Ge, Chem. Eng. J., 2025, 505, 159255.
92. M. Ren, N. Wang, L. Pu, X.-K. Ouyang and J. Mao, Int. J. Biol. Macromol., 2025, 316, 144716.
93. D. Yan, G. Cao, Y. Gao, Y. Wang, W. Zhang, K. Wang, S. Mao, C. Li, G. Zhou, H. Xia, W. Dai, X. Yan and Y. Wang, Mater. Today Bio, 2025, 31, 101554.
94. W. Li, Z. Liu, X. Tan, N. Yang, Y. Liang, D. Feng, H. Li, R. Yuan, Q. Zhang, L. Liu and L. Ge, Adv. Healthcare Mater., 2024, 13, 2304365.
95. Y. Guo, C. Zhang, B. Xie, W. Xu, Z. Rao, P. Zhou, X. Ma, J. Chen, R. Cai, G. Tao and Y. He, ACS Appl. Mater. Interfaces, 2024, 16, 33205–33222.
96. P. Ye, Y. Yang, M. Liu, J. Meng, J. Zhao, J. Zhao, J. Wang, Q. Lu, J. Liu, L. Wang, J. Lei and C. Wang, Adv. Mater., 2025, 37, 2419430.
97. X. Li, X. Xiao, Y. Zhang, R. Long, R. K. Kankala, S. Wang and Y. Liu, Int. J. Biol. Macromol., 2024, 282, 137185.
98. Y. Yang, L. Fan, J. Jiang, J. Sun, L. Xue, X. Ma, L. Kuai, B. Li and Y. Li, J. Nanobiotechnol., 2024, 22, 489.
99. P. Li, Q. Liu, M. Pei, Y. Gan, Y. Gong, C. Gong, P. Wang, M. Wang, X. Wang, D.-P. Yang, B. Liang and G. Ji, Chin. Chem. Lett., 2024, 35, 109457.
100. A. Wang, X. Ruan, X. Wang, Y. Ren, C. Shen, K. Zhang, Z. Song, B. Xiang, Y. Ma and F. Zhao, Eur. J. Pharm. Biopharm., 2024, 203, 114448.
101. X. Liu, C. Guo, W. Yang, W. Wang, N. Diao, M. Cao, Y. Cao, X. Wang, X. Wang, H. Pei, Y. Jiang, M. Kong and D. Chen, Carbohydr. Polym., 2024, 345, 122574.
102. Z. Zhang, Y. Zhang, L. Peng, Y. Xing, X. Zhou, S. Zheng, Y. Zhang and L. Shao, Mater. Today Bio, 2025, 32, 101739.
103. X. Wang, Y. Fan, J. Yan and M. Yang, Chem. Eng. J., 2022, 439, 135661.
104. S. Amit Kumar, S. Rajeev Kumar and P. Abhay Kumar, Curr. Med. Chem., 2023, 30, 3905–3926.
105. Y. Liu, G. Xia, Y. Chen, H. Xia, J. Xu, L. Guo, S. Lin and Y. Liu, Acta Pharm. Sin. B, 2023, 13, 5060–5073.
106. Q. Lu, X. Tang, B. Tao, K. Huang, K. Li, C. Liu, B. Gao, M. Xu, W. Geng, K. Li and F. Zhou, Int. J. Biol. Macromol., 2025, 296, 139685.
107. L.-y Long, W. Liu, L. Li, C. Hu, S. He, L. Lu, J. Wang, L. Yang and Y.-b Wang, Nanoscale, 2022, 14, 1285–1295.
108. Y. Yang, R. Zhou, Y. Wang, Y. Zhang, J. Yu and Z. Gu, Angew. Chem., Int. Ed., 2023, 62, e202214795.
109. X. Li, Y. Liu, J. Zhang, R. You, J. Qu and M. Li, Mater. Sci. Eng., C, 2017, 72, 394–404.
110. P. Yang, X. Wang, D. Wang, Y. Shi, M. Zhang, T. Yu, D. Liu, M. Gao, X. Zhang and Y. Liu, J. Cell Sci., 2020, 133, jcs235838.
111. M. Liu, J. You, Y. Zhang, L. Zhang, S. Quni, H. Wang and Y. Zhou, ACS Appl. Mater. Interfaces, 2024, 16, 24351–24371.
112. Z. Wang, W. Li, L. Gou, Y. Zhou, G. Peng, J. Zhang, J. Liu, R. Li, H. Ni, W. Zhang, T. Cao, Q. Cao, H. Su, Y.-P. Han, N. Tong, X. Fu, E. Ilegems, Y. Lu, P.-O. Berggren, X. Zheng and C. Wang, Adv. Healthcare Mater., 2022, 11, 2200782.
113. J. E. Allen, Annu. Rev. Immunol., 2023, 41, 229–254.
114. J. Wu, J. Zhu, Q. Wu, Y. An, K. Wang, T. Xuan, J. Zhang, W. Song, H. He, L. Song, J. Zheng and J. Xiao, ACS Appl. Mater. Interfaces, 2021, 13, 2230–2244.
115. G. Chen, N. An, W. Ye, S. Huang, Y. Chen, Z. Hu, E. Shen, J. Zhu, W. Gong, G. Tong, Y. Zhu, L. Fang, C. Cai, X. Li, K. Kim, L. Jin, J. Xiao and W. Cong, Redox Biol., 2021, 41, 101904.
116. S. Wu, B. Qin, X. Tang, T. Cui, S. Yin, H. Dong, Y. Liu, S. Deng, H. Zhang, G. Feng, H. Xie and L. Lei, Chem. Eng. J., 2023, 466, 143126.
117. Z. Le, M. C. Ramos, Y. Shou, R. R. Li, H. S. Cheng, C. J. M. Jang, L. Liu, C. Xue, X. Li, H. Liu, C. T. Lim, N. S. Tan, A. D. White, C. J. Charles, Y. Chen, Z. Liu and A. Tay, Biomaterials, 2024, 311, 122700.
118. Y. Liao, Z. Zhang, Y. Zhao, S. Zhang, K. Zha, L. Ouyang, W. Hu, W. Zhou, Y. Sun and G. Liu, Bioact. Mater., 2025, 44, 131–151.
119. X. Yu, J. Zhao, X. Ma and D. Fan, Chem. Eng. J., 2023, 465, 142933.
120. H. Sies and D. P. Jones, Nat. Rev. Mol. Cell Biol., 2020, 21, 363–383.
121. X. Zuo, X. Guo, Y. Gu, D. Zhao, Z. Zou, Y. Shen, C. He, Y. Rong, C. Xu and F. Wang, Adv. Funct. Mater., 2024, 34, 2316496.
122. Z. Cao, C. Liu, J. Wen and Y. Lu, Adv. Mater., 2024, 36, 2403116.
123. Y. Shi, X. Zhen, Y. Zhang, Y. Li, S. Koo, Q. Saiding, N. Kong, G. Liu, W. Chen and W. Tao, Chem. Rev., 2024, 124, 929–1033.
124. S. Wang, D. Weissman and Y. Dong, Nat. Rev. Drug Discovery, 2025 DOI:10.1038/s41573-025-01237-x.
125. K. A. Whitehead, R. Langer and D. G. Anderson, Nat. Rev. Drug Discovery, 2009, 8, 129–138.
126. S. Wang, Y. Zhang, Y. Zhong, Y. Xue, Z. Liu, C. Wang, D. D. Kang, H. Li, X. Hou, M. Tian, D. Cao, L. Wang, K. Guo, B. Deng, D. W. McComb, M. Merad, B. D. Brown and Y. Dong, Proc. Natl. Acad. Sci. U. S. A., 2024, 121, e2322935121.
127. Y. Xue, Y. Zhang, Y. Zhong, S. Du, X. Hou, W. Li, H. Li, S. Wang, C. Wang, J. Yan, D. D. Kang, B. Deng, D. W. McComb, D. J. Irvine, R. Weiss and Y. Dong, Nat. Commun., 2024, 15, 739.
128. D. Lou, Y. Luo, Q. Pang, W.-Q. Tan and L. Ma, Bioact. Mater., 2020, 5, 667–679.
129. J. Wang, Y. Wang, M. Lu, X. Cao, M. Xia, M. Zhao and Y. Zhao, Aggregate, 2025, 6, e700.
130. J. Wang, L. Cai, N. Li, Z. Luo, H. Ren, B. Zhang and Y. Zhao, Nano-Micro Lett., 2025, 17, 155.
131. L. Wu, Y. Wang, X. Xu, Y. Liu, B. Lin, M. Zhang, J. Zhang, S. Wan, C. Yang and W. Tan, Chem. Rev., 2021, 121, 12035–12105.
132. Y. Qian, B. Zhang, Y. Xu, J. Liang, X. Yang, Y. Gu, Z. Fan, D. Li and Y. Hu, Adv. Funct. Mater., 2025, 35, 2423012.
133. X. Li, H. Hu, H. Wang, J. Liu, W. Jiang, F. Zhou and J. Zhang, Mater. Horiz., 2025, 12, 1388–1412.
134. Z. Wang, D. Zhang, N. Liu, J. Wang, Q. Zhang, S. Zheng, Z. Zhang and W. Zhang, Int. J. Biol. Macromol., 2025, 297, 138885.
135. Y. Shou, Z. Le, H. S. Cheng, Q. Liu, Y. Z. Ng, D. L. Becker, X. Li, L. Liu, C. Xue, N. J. Y. Yeo, R. Tan, J. Low, A. R. K. Kumar, K. Z. Wu, H. Li, C. Cheung, C. T. Lim, N. S. Tan, Y. Chen, Z. Liu and A. Tay, Adv. Mater., 2023, 35, 2304638.
136. D. B. Zuo, C. H. Wang, M. Sang, X. D. Sun, G. P. Chen and K. K. Ji, World J. Diabetes, 2025, 16, 107344.
137. O. Levy, R. Kuai, E. M. J. Siren, D. Bhere, Y. Milton, N. Nissar, M. De Biasio, M. Heinelt, B. Reeve, R. Abdi, M. Alturki, M. Fallatah, A. Almalik, A. H. Alhasan, K. Shah and J. M. Karp, Sci. Adv., 2020, 6, eaba6884.
138. S. Du, D. I. Zeugolis and T. O’Brien, Stem Cell Res. Ther., 2022, 13, 426.
139. X. Wu, D. Huang, Y. Xu, G. Chen and Y. Zhao, Adv. Mater., 2023, 35, 2301064.
140. J. Lötvall, A. F. Hill, F. Hochberg, E. I. Buzás, D. Di Vizio, C. Gardiner, Y. S. Gho, I. V. Kurochkin, S. Mathivanan, P. Quesenberry, S. Sahoo, H. Tahara, M. H. Wauben, K. W. Witwer and C. Théry, J. Extracell. Vesicles, 2014, 3, 26913.
141. H. Valadi, K. Ekström, A. Bossios, M. Sjöstrand, J. J. Lee and J. O. Lötvall, Nat. Cell Biol., 2007, 9, 654–659.
142. R. Kalluri and V. S. LeBleu, Science, 2020, 367, eaau6977.
143. D. Bian, Y. Wu, G. Song, R. Azizi and A. Zamani, Stem Cell Res. Ther., 2022, 13, 24.
144. C. Théry, M. Ostrowski and E. Segura, Nat. Rev. Immunol., 2009, 9, 581–593.
145. M. D. Hade, C. N. Suire and Z. Suo, Cells, 2021, 10, 1959.
146. J. Wu, L. H. Chen, S. Y. Sun, Y. Li and X. W. Ran, World J. Diabetes, 2022, 13, 1066–1095.
147. S. Jing, H. Li and H. Xu, Int. J. Nanomed., 2023, 18, 2707–2720.
148. J. Gan, X. Zhang, W. Ma, Y. Zhao and L. Sun, Nano Today, 2022, 47, 101630.
149. H. Y. Kim, T. J. Kim, L. Kang, Y.-J. Kim, M. K. Kang, J. Kim, J. H. Ryu, T. Hyeon, B.-W. Yoon, S.-B. Ko and B.-S. Kim, Biomaterials, 2020, 243, 119942.
150. A. Grangier, J. Branchu, J. Volatron, M. Piffoux, F. Gazeau, C. Wilhelm and A. K. A. Silva, Adv. Drug Delivery Rev., 2021, 176, 113843.
151. Y. Li, Z. Zhu, S. Li, X. Xie, L. Qin, Q. Zhang, Y. Yang, T. Wang and Y. Zhang, J. Nanobiotechnol., 2024, 22, 398.
152. L. Kuang, C. Zhang, B. Li, H. Deng, R. Chen and G. Li, Int. J. Nanomed., 2023, 18, 949–970.
153. A. Geiger, A. Walker and E. Nissen, Biochem. Biophys. Res. Commun., 2015, 467, 303–309.
154. M. Li, T. Wang, H. Tian, G. Wei, L. Zhao and Y. Shi, Artif. Cells Nanomed. Biotechnol., 2019, 47, 3793–3803.
155. Y. Yu, H. Jin, L. Li, X. Zhang, C. Zheng, X. Gao, Y. Yang and B. Sun, J. Nanobiotechnol., 2023, 21, 308.
156. S. Rui, L. Dai, X. Zhang, M. He, F. Xu, W. Wu, D. G. Armstrong, Y. You, X. Xiao, Y. Ma, Y. Chen and W. Deng, J. Controlled Release, 2024, 372, 221–233.
157. X. Zhou, B. A. Brown, A. P. Siegel, M. S. El Masry, X. Zeng, W. Song, A. Das, P. Khandelwal, A. Clark, K. Singh, P. R. Guda, M. Gorain, L. Timsina, Y. Xuan, S. C. Jacobson, M. V. Novotny, S. Roy, M. Agarwal, R. J. Lee, C. K. Sen, D. E. Clemmer and S. Ghatak, ACS Nano, 2020, 14, 12732–12748.
158. H. Kim, S. Y. Wang, G. Kwak, Y. Yang, I. C. Kwon and S. H. Kim, Adv. Sci., 2019, 6, 1900513.
159. J. Zeng, Z. Sun, F. Zeng, C. Gu and X. Chen, Mater. Today Bio, 2023, 20, 100649.
160. T. Chen, P. Song, M. He, S. Rui, X. Duan, Y. Ma, D. G. Armstrong and W. Deng, Burns Trauma, 2023, 11, tkad003.
161. M. Saumell-Esnaola, D. Delgado, G. García del Caño, M. Beitia, J. Sallés, I. González-Burguera, P. Sánchez, M. López de Jesús, S. Barrondo and M. Sánchez, Int. J. Mol. Sci., 2022, 23, 2861.
162. Y. Cao, B. Chen, Q. Liu, Y. Mao, Y. He, X. Liu, X. Zhao, Y. Chen, X. Li, Y. Li, L. Liu, C. Guo, S. Liu, F. Tan, H. Lu, J. Liu and C. Chen, Bioact. Mater., 2024, 42, 32–51.
163. Y. Dai, Q. Zhang, R. Gu, J. Chen, P. Ye, H. Zhu, M. Tang and X. Nie, Int. J. Pharm., 2024, 667, 124889.
164. T. Ning, F. Yang, D. Chen, Z. Jia, R. Yuan, Z. Du, S. Liu, Y. Yu, X. Dai, X. Niu and Y. Fan, Adv. Healthcare Mater., 2022, 11, 2102180.
165. H. J. Hwang, Y. Choi, S. Kim, S. H. Lee, S. J. Choi, H.-Y. Kwon, D. Kwon, S. Park, H. Lee, M.-R. Ok, Y.-C. Kim, B.-I. Park and H.-S. Han, Nano Energy, 2024, 131, 110200.
166. P. Wang, J. Wu, H. Yang, H. Liu, T. Yao, C. Liu, Y. Gong, M. Wang, G. Ji, P. Huang and X. Wang, Bioact. Mater., 2023, 24, 463–476.
167. Y. Chen, J. Cai, D. Liu, S. Liu, D. Lei, L. Zheng, Q. Wei and M. Gao, Regener. Biomater., 2022, 9, rbac019.
168. Z. Han, L. Deng, S. Chen, H. Wang and Y. Huang, Burns Trauma, 2023, 11, tkac048.
169. J. Yang, Z. Chu, Y. Jiang, W. Zheng, J. Sun, L. Xu, Y. Ma, W. Wang, M. Shao and H. Qian, Adv. Healthcare Mater., 2023, 12, 2300725.
170. X. He, L. Peng, L. Zhou, H. Liu, Y. Hao, Y. Li, Z. lv, B. Zeng, X. Guo and R. Guo, Acta Biomater., 2024, 189, 270–285.
171. D. Yu, L. Chen, T. Yan, Y. Zhang, X. Sun, G. Lv, S. Zhang, Y. Xu and C. Li, Adv. Healthcare Mater., 2024, 13, 2301985.
172. Y. Wu, L. Yang, G. Shi, L. Zou, J. He, J. Li, A. Zhang, X. Wang, Z. Liu, K. Tang and X. Yang, Int. J. Biol. Macromol., 2025, 291, 139126.
173. Q. Xuan, J. Cai, Y. Gao, X. Qiao, T. Jin, M. Peydayesh, J. Zhou, Q. Sun, L. Zhan, B. Liu, P. Wang, H. Li, C. Chen and R. Mezzenga, Adv. Mater., 2025, 37, 2417774.
174. W. You, Z. Cai, F. Xiao, J. Zhao, G. Wang, W. Wang, Z. Chen, W. Hu, Y. Chen and Z. Wang, Adv. Sci., 2025, 12, 2417314.
175. G. Guan, Q. Zhang, Z. Jiang, J. Liu, J. Wan, P. Jin and Q. Lv, Small, 2022, 18, 2203064.
176. W. Zhu, Q. Liu, Z. Zhang, Y. Wang, J. Mei, D. Xu, J. Zhou, Z. Su, X. Zhang, C. Zhu, J. Wang, J. Zhu, X. Peng and X. Zhang, Small Struct., 2024, 5, 2400014.
177. L. Chen, P. Cao, P. Zhao, Y. Xu, G. Lv and D. Yu, Mater. Des., 2024, 241, 112971.
178. M. Li, H. Jafari, O. V. Okoro, L. Nie and A. Shavandi, Cell Biomater., 2025, 1, 100049.
179. Y. G. Kim, Y. Lee, N. Lee, M. Soh, D. Kim and T. Hyeon, Adv. Mater., 2024, 36, 2210819.
180. L. Yang, S. Dong, S. Gai, D. Yang, H. Ding, L. Feng, G. Yang, Z. Rehman and P. Yang, Nano-Micro Lett., 2023, 16, 28.
181. W. Zhang, S. Hu, J.-J. Yin, W. He, W. Lu, M. Ma, N. Gu and Y. Zhang, J. Am. Chem. Soc., 2016, 138, 5860–5865.
182. X. Zhang, Z. Li, P. Yang, G. Duan, X. Liu, Z. Gu and Y. Li, Mater. Horiz., 2021, 8, 145–167.
183. M. Lu, M. H. Cohen, D. Rieves and R. Pazdur, Am. J. Hematol., 2010, 85, 315–319.
184. Y. Guo, Y. Li, R. Fan, A. Liu, Y. Chen, H. Zhong, Y. Liu, H. Chen, Z. Guo and Z. Liu, Nano Lett., 2023, 23, 8761–8769.
185. Q. Yang, J. Yang, X. Liu, Y. Zhang, Y. Li, D. Ao, P. Zhong and K. Yong, Biol. Trace Elem. Res., 2023, 201, 4419–4428.
186. K. Lv, S. Zhang, Z. Yao, C. Zhou and J. Xu, Int. J. Nanomed., 2025, 20, 8907–8934.
187. H. Ge, M. Wang, X. Wei, X.-L. Chen and X. Wang, Small, 2025, 21, 2407195.
188. J. Ding, K. Xu, H. Xu, J. Ji, Y. Qian and J. Shen, Small Struct., 2024, 5, 2300151.
189. I. Ohsawa, M. Ishikawa, K. Takahashi, M. Watanabe, K. Nishimaki, K. Yamagata, K.-I. Katsura, Y. Katayama, S. Asoh and S. Ohta, Nat. Med., 2007, 13, 688–694.
190. H. Chen, Y. Guo, Z. Zhang, W. Mao, C. Shen, W. Xiong, Y. Yao, X. Zhao, Y. Hu, Z. Zou and J. Wu, Nano Lett., 2022, 22, 229–237.
191. Y. Zhu, Q. Jiang, Z. Jin, D. Chen, Q. Xu, J. Chen, Y. Zeng, S. Chen and Q. He, Adv. Healthcare Mater., 2023, 12, 2201705.
192. H. Tao, Y. Xia, T. Tang, Y. Zhang, S. Qiu, J. Chen, Z. Xu, L. Li, J. Qiu, P. Wang, J. Wu, X. Zhao, S. Xu and G. Wang, Chem. Eng. J., 2024, 489, 151200.
193. Z. Cheng and R. Kishore, Redox Biol., 2020, 37, 101704.
194. J. Wu, A. Chen, Y. Zhou, S. Zheng, Y. Yang, Y. An, K. Xu, H. He, J. Kang, J. A. Luckanagul, M. Xian, J. Xiao and Q. Wang, Biomaterials, 2019, 222, 119398.
195. G. Cai, R. Li, X. Chai, X. Cai, K. Zheng, Y. Wang, K. Fan, Z. Guo, J. Guo and W. Jiang, J. Colloid Interface Sci., 2024, 667, 529–542.
196. J. Chen, D. Chen, J. Chen, T. Shen, T. Jin, B. Zeng, L. Li, C. Yang, Z. Mu, H. Deng and X. Cai, Acta Biomater., 2022, 146, 49–65.
197. L. Cao, C. Liu, C. Mu, Q. Li, M. Wu, L. Liu and B. Liu, Adv. Healthcare Mater., 2025, 14, 2402910.
198. M. J. Malone-Povolny, S. E. Maloney and M. H. Schoenfisch, Adv. Healthcare Mater., 2019, 8, 1801210.
199. Y. Zhao, L. Luo, L. Huang, Y. Zhang, M. Tong, H. Pan, J. Shangguan, Q. Yao, S. Xu and H. Xu, J. Controlled Release, 2022, 350, 93–106.
200. S. Y. Silva, L. C. Rueda, G. A. Márquez, M. López, D. J. Smith, C. A. Calderón, J. C. Castillo, J. Matute, C. F. Rueda-Clausen, A. Orduz, F. A. Silva, P. Kampeerapappun, M. Bhide and P. López-Jaramillo, Trials, 2007, 8, 26.
201. M. E. Edmonds, H. J. Bodansky, A. J. M. Boulton, P. J. Chadwick, C. N. Dang, R. D'Costa, A. Johnston, B. Kennon, G. Leese, S. M. Rajbhandari, T. E. Serena, M. J. Young, J. E. Stewart, A. T. Tucker and M. J. Carter, Wound Repair Regen., 2018, 26, 228–237.
202. Y. Zeng, C. Wang, J. Lei, X. Jiang, K. Lei, Y. Jin, T. Hao, W. Zhang, J. Huang and W. Li, Acta Pharm. Sin. B, 2024, 14, 5037–5052.
203. Q. Li, B. Li, R. Yang, X. Chen, C. Shang, G. Feng, Z. Wu, Y. Teng, H. He, Y. Bai and B. Zheng, Cell Biomater., 2025, 1, 100047.
204. E. Zhao, T. Xiao, Y. Tan, X. Zhou, Y. Li, X. Wang, K. Zhang, C. Ou, J. Zhang, Z. Li and H. Liu, ACS Appl. Mater. Interfaces, 2023, 15, 7725–7734.
205. S. Gao, Y. Rao, X. Wang, Q. Zhang, Z. Zhang, Y. Wang, J. Guo and F. Yan, Adv. Mater., 2024, 36, 2307585.
206. C. Liu, K. Liu, D. Zhang, Y. Liu, Y. Yu, H. Kang, X. Dong, H. Dai and A. Yu, Bioact. Mater., 2025, 46, 213–228.
207. H.-H. Chen, F.-S. Fu, Q.-W. Chen, Y. Zhang and X.-Z. Zhang, Nano Lett., 2023, 23, 5595–5602.
208. R. Luo, J. Dai, J. Zhang and Z. Li, Adv. Healthcare Mater., 2021, 10, 2100557.
209. B. Tandon, A. Magaz, R. Balint, J. J. Blaker and S. H. Cartmell, Adv. Drug Delivery Rev., 2018, 129, 148–168.
210. G. Pace, A. E. del Rio Castillo, A. Lamperti, S. Lauciello and F. Bonaccorso, Adv. Mater., 2023, 35, 2211037.
211. X. Xiao, eScience, 2022, 2, 1–9.
212. X. Zhang, Z. Wang, H. Jiang, H. Zeng, N. An, B. Liu, L. Sun and Z. Fan, Sci. Adv., 2023, 9, eadh1415.
213. L. Ulloa, S. Quiroz-Gonzalez and R. Torres-Rosas, Trends Mol. Med., 2017, 23, 1103–1120.
214. Y. Hou, X. Guo, J. Ran, X. Lu and C. Xie, Bioact. Mater., 2025, 44, 516–530.
215. Y. Deng, J. Zheng, J. Li, B. Liu, K. Chen, Y. Xu, L. Deng, H. Liu and Y.-N. Liu, Theranostics, 2025, 15, 3474–3489.
216. R. Xie, D. Fan, Y. Fang, T. Zhu, H. Li, Y. Yin, X. Liu, Y. Ma, F. Chen and W. Zeng, Adv. Healthcare Mater., 2025, 14, 2405190.
217. Z. Wang, B. Li, C. Nie, R. Zhang, S. Qu, Q. Shao, X. Zhang, J. Li, W. Li, H. Li, J. Xiao and C. Xing, Nano Lett., 2025, 25, 2911–2921.
218. R. Zhang, J. Feng, H. Chen, G. Zhang, X. Liang, C. Xu, Y. Li and F.-J. Xu, Adv. Funct. Mater., 2025, 35, 2419170.
219. Y. Wu, L. Ma, Y. Tan, Q. Tong, D. Liu, X. Zheng, Z. Yi, J. Chen and X. Li, Chem. Eng. J., 2025, 509, 161400.
220. K. Mao, M. Yue, H. Ma, Z. Li and Y. Liu, Adv. Mater., 2025, 37, 2501817.
221. P. Makvandi, R. Jamaledin, G. Chen, Z. Baghbantaraghdari, E. N. Zare, C. Di Natale, V. Onesto, R. Vecchione, J. Lee, F. R. Tay, P. Netti, V. Mattoli, A. Jaklenec, Z. Gu and R. Langer, Mater. Today, 2021, 47, 206–222.
222. X. Chen, X. Li, X. Xiao, R. Long, B. Chen, Y. Lin, S. Wang and Y. Liu, ACS Appl. Bio Mater., 2024, 7, 6603–6616.
223. L. Lu, J. Liao, C. Xu, Y. Xiong, J. Zhou, G. Wang, Z. Lin, K. Zha, C. Lin, R. Zeng, G. Dai, Q. Feng, B. Mi and G. Liu, Adv. Sci., 2025, 12, 2502293.
224. Z. Zeng, G. Jiang, Y. Sun, U. E. Aharodnikau, K. E. Yunusov, X. Gao, T. Liu and S. O. Solomevich, Biomater. Sci., 2022, 10, 5326–5339.
225. S. Gao, W. Zhang, X. Zhai, X. Zhao, J. Wang, J. Weng, J. Li and X. Chen, Biomater. Sci., 2023, 11, 533–541.
226. X. Wu, D. Xia, T. Shi, B. Li, D. Wang, C. Liang and M. Dong, J. Mater. Sci. Technol., 2025, 205, 299–314.
227. Y. Xue, C. Chen, R. Tan, J. Zhang, Q. Fang, R. Jin, X. Mi, D. Sun, Y. Xue, Y. Wang, R. Xiong, H. Lu and W. Tan, ACS Appl. Mater. Interfaces, 2022, 14, 37396–37409.
228. L. Yuan, Q. He, Y. Zhang, H. Luo, W. Xiang, C. Deng, C. Li, X. Li, L. Yao, D. Ke, S. Wang, J. Zhou and J. Wang, Int. Immunopharmacol., 2025, 151, 114288.
229. B. Hou, A. Xu, S. Zhang, W. Cai, Y. Wen, Y. Wang, X. Zhu, S. Huang, J. Huang, L. Qiu and H. Sun, Int. J. Biol. Macromol., 2025, 310, 143471.
230. Y. Liu, M. Zhou, J. Sun, E. Yao, J. Xu, G. Yang, X. Wu, L. Xu, J. Du and X. Jiang, Adv. Sci., 2024, 11, 2404130.
231. Y. Yang, N. Chen, J. Fan, L. Fan, Y. Cai, L. Xue, S. Chen, Z. Yang, L. An, J. Cheng, T. Ren and Y. Li, Small, 2025, 21, 2505179.
232. A. Younas, Z. Dong, Z. Hou, M. Asad, M. Li and N. Zhang, Carbohydr. Polym., 2023, 306, 120593.
233. X. Hou, H. Wang, X. Yao, Q. Zhou and X. Niu, ACS Nano, 2025, 19, 17709–17727.
234. Z. Guo, H. Liu, Z. Shi, L. Lin, Y. Li, M. Wang, G. Pan, Y. Lei and L. Xue, J. Mater. Chem. B, 2022, 10, 3501–3511.
235. Z.-M. Zhuang, Y. Wang, L. Chen, Z.-R. Wu, T. Zhang, H.-P. Bei, Z.-X. Feng, Y. Wang, K. Guo, Y.-Y. Hsu, J. Chen, Y.-Z. Du, J. Chen, X. Zhao, N.-W. Zhu and W.-Q. Tan, Biomaterials, 2026, 324, 123520.
236. X. Zhang, J. Gan, L. Fan, Z. Luo and Y. Zhao, Adv. Mater., 2023, 35, 2210903.
237. Q. Zeng, Y. Zhang, J. Zheng, J. Lin, N. Li, M. Zhao, X. Chen, X. Li, M. Zhao, J. Huang, Q. Xie, R. Yang, Y. Jiang, X. Zou and Y. Liao, Chem. Eng. J., 2025, 505, 159239.
238. D. Wu, X. Wu, Q. Luan, Q. Tang, L. Fan, X. Shou, X. Gao, X. Qian and Y. Zhao, Chem. Eng. J., 2024, 493, 152252.
239. L. Yang, D. Zhang, W. Li, H. Lin, C. Ding, Q. Liu, L. Wang, Z. Li, L. Mei, H. Chen, Y. Zhao and X. Zeng, Nat. Commun., 2023, 14, 7658.
240. D. He, X. Liu, J. Jia, B. Peng, N. Xu, Q. Zhang, S. Wang, L. Li, M. Liu, Y. Huang, X. Zhang, Y. Yu and G. Luo, Adv. Funct. Mater., 2024, 34, 2306357.
241. Q. Zhou, X. Li, N. Gao, G. Ling and P. Zhang, J. Mater. Chem. B, 2024, 12, 1007–1021.
242. M. Li, Y. Dong, Y. Shang, J. Liu, Y. Wang, D. Zhang, L. Zhang, C. Han, Y. Zhang, K. Shen, Y. Yang, H. Wang, H. Guan and D. Hu, Small, 2024, 20, 2407802.
243. S. Tian, J. Mei, L. Zhang, S. Wang, Y. Yuan, J. Li, H. Liu, W. Zhu and D. Xu, Small, 2024, 20, 2407340.
244. J. Zhang, X. Luo, Y. Hu, B. Gao, X. Tang, S. Fang, B. Ou, X. Sheng, J. Su and J. Feng, Small, 2025, 21, 2505277.
245. S. Deng, Y. Tai, C. Liu, K. Sun, S. Lan, L. Yang, C. Ye, L. Huang, R. Yang, H. Qian and J. Li, Mater. Today Bio, 2025, 32, 101903.
246. P. Wang, Y. Pu, Y. Ren, W. Kong, L. Xu, W. Zhang, T. Shi, J. Ma, S. Li, X. Tan and B. Chi, Int. J. Biol. Macromol., 2023, 226, 813–822.
247. X. Su, X. Geng, F. Li, M. Song, R. Lv, Y. Zhang, J. Yuan, J. Dong, Y. Shi and L. Zhao, J. Colloid Interface Sci., 2025, 691, 137353.
248. M. Sun, X. Zhong, M. Dai, X. Feng, C. Tang, L. Cao and L. Liu, Mater. Today Bio, 2024, 24, 100945.
249. X. Zhang, G. Chen, Y. Liu, L. Sun, L. Sun and Y. Zhao, ACS Nano, 2020, 14, 5901–5908.
250. H. Shen, Y. Ma, C. Zhang, Y. Qiao, J. Chen and F. Sun, ACS Appl. Nano Mater., 2024, 7, 15171–15184.

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