Advances of Chinese herbal medicine-derived polysaccharides as carrier-free and carrier agents in anti-melanoma therapy

Abstract

Melanoma, a highly aggressive malignancy with increasing global incidence, faces significant therapeutic challenges due to drug resistance, systemic toxicity, and immunosuppressive tumor microenvironment. Despite advances in targeted therapies and immunotherapies, the need for safer and more effective treatment options remains urgent. Chinese herbal medicine-derived polysaccharides (CHMPs), characterized by their natural origin, biocompatibility, and multifaceted bioactivities, have garnered increasing attention as promising candidates for melanoma therapy due to their low toxicity and multi-targeting capabilities. In this review, the dual roles of CHMPs with varied origins in anti-melanoma treatment will be systematically elucidated. As carrier-free anti-tumor agents, CHMPs exert anti-melanoma effects through multiple mechanisms, including immune modulation, apoptosis induction, cell cycle arrest, inhibiting tumor angiogenesis, and regulating signaling pathways. Moreover, as intelligent carriers, CHMPs can be chemically modified or physically assembled into targeted delivery systems, enhancing drug stability and bioavailability while minimizing off-target toxicity. Finally, current challenges for CHMPs in anti-melanoma treatments, such as structural heterogeneity, unclear structure–activity relationships, and limited clinical translation, will be outlined, and future efforts are also discussed. By bridging traditional herbal medicine and modern biomaterials science, we expect this review not only to provide a roadmap for developing CHMP-based multifunctional biomaterials platforms but also to inspire novel strategies to overcome current therapeutic bottlenecks in melanoma management, paving the way for safer and more effective treatments.

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Yingmin Mao

Yingmin Mao received his master's degree from Changchun University of Chinese Medicine in 2023. Since the autumn of 2024, he has been pursuing his doctoral studies under the supervision of Professor Quan Li. His research primarily focuses on the functional development of soft matter materials derived from Chinese herb medicine.

Quan Li

Quan Li obtained his PhD in Chemistry from the University of Strasbourg, France, in 2015. He subsequently pursued postdoctoral research at Dartmouth College, USA (2015–2018). Currently, he is a Professor and Doctoral Supervisor at the School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, where his research mainly focuses on soft matter from Chinese herbal medicine and molecular engineering of dynamic drugs.

Hanming Cui

Hanming Cui obtained his master's degree in pharmacy from Peking University Health Science Center. He is now a research professor at the New Drug Research and Development Center of Guang’anmen Hospital, China Academy of Chinese Medical Sciences. His research mainly focuses on the action mechanism of traditional Chinese medicine (TCM) formulas and the development of new TCM drugs. He has led and taken part in over 20 national and ministerial-level projects, published more than 60 papers, and been granted 10 patents.

Yue Liu

Yue Liu is currently an associate professor at Beijing University of Chinese Medicine. He obtained his PhD in Natural Product Chemistry at Shenyang Pharmaceutical University in 2013. He undertook post-doctoral research at the National Institutes for Food and Drug Control from 2016 to 2019. His research mainly focuses on the active natural products of traditional Chinese herbs and the quality evaluation of TCM.

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1. Introduction

Melanoma is a highly aggressive malignant tumor originating from melanocytes, with a propensity for early metastasis to lymph nodes and distant organs such as the lungs and liver.¹ According to data from the International Agency for Research on Cancer (IARC), there were 331 722 newly reported cases of melanoma and 58 667 deaths globally in 2022.² It is anticipated that the global incidence and mortality of melanoma will continue to rise by 2040.³ Currently, several therapeutic strategies have been employed in clinics to treat melanoma. Surgical resection is the preferred treatment for early-stage, localized melanoma. Nevertheless, it is associated with a relatively high postoperative recurrence rate and is unsuitable for metastatic cases.⁴ Radiotherapy is routinely employed as an adjuvant treatment post-surgery or to alleviate symptoms of metastatic lesions. However, melanoma exhibits low sensitivity to radiation, and the treatment carries a risk of damaging surrounding healthy tissues.¹ Targeted therapies, including BRAF inhibitors, have significantly improved the prognosis of patients with BRAF mutations. Nevertheless, approximately 50% of patients may develop acquired resistance (e.g., NRAS mutations) and experience disease recurrence within one year.⁵ Immune checkpoint blockade therapies, including PD-1 antibodies, enhance survival by activating T cell-mediated anti-tumor immune responses. But they are effective in only 20–40% of patients and may induce immune-related adverse events, such as colitis and pneumonitis.⁶ Conventional chemotherapeutic agents, including dacarbazine, are often associated with bone marrow suppression and hepatorenal toxicity due to their lack of target specificity.⁷ Thus, the limitations of these clinical strategies highlight the urgency to develop novel therapeutic approaches featuring high efficacy and improved safety profiles.

Chinese herbal medicine-derived polysaccharides (CHMPs), a class of naturally occurring polymers, have gained increasing attention as multi-functional and bioactive agents with distinctive therapeutic advantages in cancer treatment.⁸ These natural polymers, extracted from varied bio-resources such as plants,⁹ fungi,¹⁰ and marine algae,¹¹ have exhibited remarkable anti-cancer activity and high biocompatibility (Fig. 1a), but low systemic toxicity, making them exceptional scaffolds for cancer treatment. Currently, structurally diversified CHMPs themselves have demonstrated direct anti-melanoma effects through apoptosis induction,¹² cell cycle arrest,¹³ and inhibition of angiogenesis and metastasis.¹⁴ Furthermore, CHMPs orchestrate a multimodal immunomodulatory network by cooperatively activating T cells, B cells, and dendritic cells (DCs) to reprogram the immunosuppressive tumor microenvironment,¹⁵ augment the cytotoxic effector functions of natural killer (NK) cells,⁹ and drive the repolarization of tumor-associated macrophages (TAMs) toward a pro-inflammatory M1 phenotype (Fig. 1b).¹⁶ This integrated immunoregulatory cascade establishes a comprehensive antitumor immune response. Meanwhile, CHMPs also exhibit remarkable synergistic effects when combined with other anti-melanoma drugs.¹⁶ Additionally, CHMPs have also emerged as versatile carrier platforms for building advanced drug delivery systems, due to their unique physicochemical properties and biocompatibility. The tunable physicochemical properties of CHMPs, particularly their hydroxyl-rich backbones, facilitate the molecular engineering of diverse drug delivery platforms, including nanoparticles,¹⁷ nanovaccines,¹⁸ microneedles,¹⁹ and hydrogels,⁴ further enabling the targeted co-delivery of chemotherapeutic agents and immunomodulators with improved pharmacokinetics, reduced systemic toxicity, and amplified anti-tumor immunity through precise spatiotemporal control (Fig. 1c).

Fig. 1 (a) Main sources of CHMPs. (b) CHMPs activate T cells, B cells, DCs, NK cells, and M1 macrophages to remodel the tumor immune microenvironment. (c) CHMP-based delivery platforms including nanoparticle, nanovaccine, hydrogels and microneedles. (d) Structural hierarchy of polysaccharides, exemplified by linear chain, branched, and triple-helix conformations.

The high renewability, easy availability, good biocompatibility, and particularly the dual roles of being drugs or drug carriers of CHMPs have highlighted their great potential for anti-melanoma therapy. In this review, the recent advances of CHMPs in anti-melanoma therapy will be focused on. Firstly, as carrier-free macromolecular agents, the origin of different CHMPs is briefly summarized, and in particular their mechanism of anti-melanoma action is systematically discussed. Then, how CHMPs can be engineered into different types of carriers, including nanoparticles, nanovaccines, microneedles, and hydrogels for the delivery of anti-melanoma drugs will be illustrated. Through the demonstration of carrier-free and drug-carrier roles played by CHMPs in anti-melanoma therapy, it is expected that our current review may offer unlimited inspiration for developing novel anti-melanoma therapeutics by identifying and engineering macromolecules from traditional-valued herbal medicines.

2. CHMPs as carrier-free agents for anti-melanoma treatment

2.1. Resources of polysaccharides

Plants contain a diverse array of bioactive natural products, among which polysaccharides have demonstrated remarkable therapeutic potential and are considered promising candidates as alternatives to conventional pharmaceutical agents.²⁰ Plants serve as the primary source of CHMPs, offering abundant raw materials for polysaccharide production.²¹ Plant-derived polysaccharides are ubiquitously present in various botanical tissues, including roots, stems, leaves, fruits, etc.²² Typical examples of CHMPs with anti-melanoma activity include Astragalus polysaccharides (APS),²³ Dendrobium officinale polysaccharides (DOP),⁴ Gynostemma pentaphyllum polysaccharides (GP-B1),²⁴ and neutral Lycium barbarum polysaccharides (NLBP)²⁵ (Table S1). Substantial evidence has established their potent anti-melanoma efficacy. For instance, the dual anti-melanoma and immunomodulatory properties of GP-B1 were demonstrated by Li et al., positioning it as a representative candidate for detailed mechanistic exploration. GP-B1 has demonstrated remarkable efficacy in suppressing B16 melanoma tumor growth in mouse models, achieving an inhibition rate of 62.5%.²⁴ It is worth noting that during the process of inhibiting tumor growth, GP-B1 does not damage the immune function of tumor-bearing mice, and its spleen index is significantly higher than that of the Cytoxan group.²⁴

Moreover, fungi also serve as a sustainable source of CHMPs, as they can be cultivated on various substrates, e.g., agricultural waste, thereby enabling cost-effective and environmentally benign polysaccharide production.²⁶ Notably, fungal-derived polysaccharides (Table S1) have illustrated multiple bioactive properties, with their antitumor and immunomodulatory effects being of particular research interest.²⁷ For example, dual anti-melanoma effects of Flammulina velutipes stipe polysaccharides (FVSP), including direct inhibition of B16-F10 melanoma cell proliferation and enhancement of anti-tumor activity through activation of RAW264.7 macrophage proliferation and phagocytosis, were demonstrated by Chen et al.²⁸ Additionally, Wang et al. have demonstrated that Ganoderma formosanum polysaccharides (PS-F2) significantly inhibited B16 melanoma growth in murine models by activating both CD4⁺ and CD8⁺ T cells, resulting in a 23.7% reduction in average tumor weight.²⁹

In addition, marine environments have offered a valuable repository of cost-effective natural biomaterials. Particularly noteworthy are polysaccharides, which constitute major structural components of algal cell walls and have attracted significant scientific interest due to their structural diversity and impressive antitumor activities.³⁰ Within this context, marine algae emerge as a pivotal source of CHMPs, as exemplified by Sargassum fusiforme polysaccharides (SFPS)¹¹ and Saccharina cichorioides laminaran (ScL)³¹ (Table S1). ScL has exhibited potent inhibitory effects on SK-MEL-28 melanoma cell viability.³¹ To enhance its therapeutic potential, ScL underwent a carboxymethylation reaction, yielding the modified derivative carboxymethylated Saccharina cichorioides laminaran (ScLCM). This structural modification substantially increased its molecular weight (M_w) and negative charge density, strengthening its interaction with cell surface receptors and consequently elevating its antitumor efficacy.³¹

2.2. Structure–activity relationship of CHMPs

The structural complexity of CHMPs, encompassing both primary and higher-order structures, is fundamentally linked to their biological activities and critically determines their in vivo mechanisms and therapeutic efficacy.⁸ The primary structure of CHMPs is typically characterized by molecular weight (M_w), monosaccharide composition, glycosidic linkage sequences, and key determinants of glycan topology, such as glycosidic bond positions, anomeric configurations, and spatial distribution of substituents. These fundamental parameters collectively define the chemical identity of polysaccharides.²² The higher-order structure further comprises chain dimensions, morphological features, three-dimensional conformations, and supramolecular assembly states, representing dynamic hierarchical manifestations of glycan topological architecture (Fig. 1d).²⁶ The remarkable bio-diversity of CHMPs is underpinned by this structural hierarchy, which accounts for the distinct anti-melanoma effects that may be exhibited by different polysaccharides isolated from the same medicinal plant.

A well-defined structure–activity relationship correlated with hierarchical structural characteristics is exhibited in the anti-melanoma efficacy of CHMPs. M_w is regarded as a fundamental parameter that significantly influences polysaccharide solubility and cellular internalization efficiency. Low-M_w fractions, including Astragalus polysaccharides (APS, 12.2 kDa),³² Angelica sinensis polysaccharides (APS-4II, 11.1 kDa),¹³ and Saposhnikovia divaricata polysaccharides (SDNP-2, 5.2 kDa)³³ were found to enhance immunomodulatory capacity and superior anti-melanoma activity due to their improved membrane permeability. Enzymatic hydrolysis of Cuscuta chinensis polysaccharides (CPS) by mannanase yields enzymatically hydrolyzed Cuscuta chinensis polysaccharides (ECPS) with reduced M_w (from 434.6 kDa to 211.7 kDa), whose increased cellular permeability and solubility facilitate targeted intracellular delivery, thereby exhibiting stronger antioxidant and anti-melanogenic effects.³⁴ Nevertheless, the anti-melanoma activity of CHMPs is not exclusively determined by M_w. This is evidenced by Dioscorea opposita polysaccharides (CYS-1, CYS-2), where CYS-1 (41 kDa) has demonstrated superior inhibitory activity against B16 melanoma cells compared to lower-M_w variants CYS-2 (23 kDa), indicating that anti-melanoma mechanisms require integrated analysis of hierarchical structural parameters.³⁵

Monosaccharide composition and charge properties can essentially regulate CHMPs’ targeting modalities. For example, uronic acid-deficient Panax ginseng polysaccharides (GP-n, low M_w: 10.3 kDa and 1.7 kDa) can be readily degraded and fermented by gut microbiota, modulating microbial composition to exert significant anti-melanoma effects.³⁶ In contrast, uronic acid-rich Panax ginseng polysaccharides (GP-a, 972.8 kDa) display a complex structure that resists microbial degradation and consequently lacks anti-melanoma activity.³⁶ Ginseng berry polysaccharides (GBPP-I, 76 kDa) with a uronic acid content of 10.4%,³⁷ and Gynostemma pentaphyllum polysaccharides (GP-B1, 79 kDa) with a uronic acid content of 10.7%,²⁴ both exhibit moderate uronic acid levels and high contents of galactose (Gal) and arabinose (Ara). In contrast, Gynostemma pentaphyllum polysaccharides (GP-C1, 126 kDa) are characterized by an elevated uronic acid content of 18.2% and low galactose and arabinose content.²⁴ GP-C1 demonstrates preferential binding to extracellular matrix components. This behavior is attributed to its strong negative surface charge and steric hindrance effects arising from its extended polymer conformation.²⁴ The low Gal and Ara content in GP-C1 may contribute to its reduced ability to interact with immune cells, potentially limiting its immunomodulatory activity and anti-tumor effects compared to GP-B1. In another case, neutral Lycium barbarum polysaccharides (NLBP) with a molecular weight of 83.4 kDa exhibit distinct structural characteristics, including a relatively high arabinose content, minimal uronic acid residues, and a porous sponge-like morphology (Fig. 2a and c). This kind of morphological feature contributes to an enlarged receptor contact interface and enhanced binding valency, thereby facilitating receptor clustering and subsequent signal transduction, which in turn drives macrophage polarization. Conversely, acidic Lycium Barbarum polysaccharides (ALBP, 37.4 kDa; 53.02% uronic acids) show constrained receptor binding (Fig. 2b and d).²⁵

Fig. 2 Scanning electron microscopy (SEM) image of NLBP (a) and ALBP (b) at 2000× magnification. Scale bar: 10 μm. SEM image of NLBP (c) and ALBP (d) at 10000× magnification. Scale bar: 2.5 μm. Adapted with permission from ref. 25. Copyright 2024 Elsevier.

The receptor recognition specificity of CHMPs was found to be modulated by glycan topology through different spatial arrangement patterns. For example, the linear (1→4)-α-D-glucan configuration of alkaline-extracted polysaccharides from Cordyceps sinensis (AIPS, 1150 kDa) confers significantly stronger anti-melanoma activity than the highly branched water-extracted polysaccharides from Cordyceps sinensis (WIPS, 1180 kDa) with comparable M_w.³⁷ Saposhnikovia divaricata polysaccharides (SDNP-2, 5.2 kDa) contain a (1→3)/(1→6)-linked Galp backbone (1 : 3 ratio) with 60% degree of branching and complex side chains (terminal Araf and (1→5)-linked Araf at O-3/O-4 positions). These structural characteristics have enabled effective engagement with immune receptors, thereby counteracting immunosuppression. In contrast, Saposhnikovia divaricata polysaccharides (SDNP-1, 67.9 kDa) with a simplistic backbone and low degree of branching fail to activate immune pathways.³³

Collectively, it has been studied that the anti-melanoma activity of CHMPs is dependent on their multi-scale structural features. The structural stability of CHMPs' higher-order assemblies has also been proven to be critical for sustaining long-term anti-melanoma efficacy. Among Bletilla striata polysaccharides (BSP-1, BSP-2), BSP-1 (269.1 kDa) has exhibited significantly greater bioactivity than the lower molecular weight variant BSP-2 (57.4 kDa). The stable triple-helix conformation of BSP-1 mediated by (1→4)-glycosidic bonds and composed of glucose, mannose, and galactose (Fig. 3a) differs from the compromised structural integrity of BSP-2, which arises from reduced M_w and simplified branching. This structural hierarchy of BSP-1 is further corroborated by the putative molecular model (Fig. 3b) and field emission scanning electron microscopy (FESEM) imaging (1000×, Fig. 3c), revealing that BSP-1's intertwined branches and flake-like or coiled surface morphologies are directly attributed to its conformational stability and functional potency.³⁸

Fig. 3 (a) and (b) Putative structure of BSP-1. (c) Field emission scanning electron microscopy (FESEM) image of BSP-1 at 1000× magnification. Adapted with permission from ref. 38. Copyright 2024 Elsevier.

2.3. Mechanism of anti-melanoma activity of CHMPs

2.3.1. Inhibits melanin production. Melanoma originates from the malignant transformation of melanocytes, with its proliferative and metastatic properties being intimately associated with key physiological pathways of melanogenesis.^1,39,40 Current research has demonstrated that targeted modulation of melanin synthesis pathways can effectively inhibit tumor progression. Within melanosomes, the multistage enzymatic reactions mediated by tyrosinase (TYR) and tyrosinase-related proteins 1/2 (TYRP1/2) constitute the core process of melanin synthesis, while the microphthalmia-associated transcription factor (MITF) serves as a central regulator by controlling the expression of TYR, TYRP1/2, and related genes.^41,42 The motor proteins Rab27A and myosin serve as established markers for melanin transport vesicle trafficking.⁴³ Numerous CHMPs exert antitumor effects by targeting critical nodes of this pathway. For instance, Saussurea involucrata polysaccharides (SIP) can significantly downregulate the expression of MITF, TYR, and TYRP1/2 by inhibiting CREB phosphorylation and modulating the JNK-MAPK/β-catenin signaling axis.⁴⁴ Ganoderma lucidum polysaccharides (GLP) can simultaneously suppress melanogenic genes (MITF, TYR, TYRP1/2) and transport genes (Rab27A/Myosin) through dual inhibition of cAMP/PKA pathway-induced CREB phosphorylation and the ROS/MAPK pathway.⁴⁵ Enzymatically hydrolyzed Cuscuta chinensis polysaccharides (ECPS) were proven to counteract α-MSH-stimulated increases in melanin content in B16F10 cells while inhibiting MITF, TYR, and TYRP1 protein expression.³⁴ Notably, Bletilla striata polysaccharides (BSP) were shown to reduce melanin synthesis by inhibiting TYR activity while concurrently suppressing B16F10 cell proliferation and metastasis.³⁸ Furthermore, the pigmented phenotype of SKMel-188 cells can be reversibly modulated by L-tyrosine concentration, whereas Coriolus versicolor-derived protein-bound polysaccharides (PBPs) can selectively inhibit non-pigmented phenotypes through mechanisms involving increased lactate dehydrogenase (LDH) release and activation of the RIP1 kinase/ROS/JNK pathway, independent of the Bcl-2/caspase pathway.⁴⁶ Other studies have revealed that Tremella fuciformis polysaccharides (TFPS) could inhibit nuclear translocation of sterol regulatory element-binding protein (SREBP), thereby reducing expression of lipogenic enzymes, including acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), which subsequently compromises melanosome membrane stability and indirectly suppresses melanin synthesis.⁴⁷

2.3.2. Induction of apoptosis in melanoma cells. CHMPs can suppress melanoma via multi-layered apoptotic regulatory networks, which engage both canonical (intrinsic mitochondrial) and non-canonical (immune-mediated and metabolic stress-induced) programmed cell death pathways. Within the classical apoptotic pathway, exopolysaccharides fraction of Cordyceps sinensis (EPSF),⁴⁸ Lycium barbarum active glycopeptides (LBAG),⁴⁹ Lycopus lucidus polysaccharides (LLP),⁵⁰ and Zizyphus jujuba polysaccharides (DPP)⁵¹ were evidenced to promote mitochondrial outer membrane permeabilization by upregulating pro-apoptotic Bax while suppressing anti-apoptotic Bcl-2 expression, triggering cytochrome c release that binds to Apaf-1 to form the apoptosome, thereby activating caspase-9 and initiating caspase-3-mediated apoptosis execution.⁵² Agaricus bisporus cell-wall polysaccharides (Abwp) were shown to enhance cleaved-PARP expression following caspase-3 activation,⁵³ while Lentinan (LNT) reverses Bcl-2's anti-apoptotic function via Nur77-AKT pathway inhibition, concomitant with increased PARP1 cleavage.⁵⁴ Coriolus versicolor polysaccharides (CVP) were found to disrupt Bcl-2/Bak interactions through p53 activation, amplifying mitochondrial apoptotic signaling,⁵⁵ and Alocasia cucullata polysaccharides (PAC) were shown to induce B16F10 cell apoptosis by modulating ERK1/2, JNK1, and p38 expression to activate MAPK signaling.¹² In non-canonical pathways, Ganoderma lucidum polysaccharides (GLP) were found to activate cytotoxic T lymphocytes (CTLs) to release perforin/granzyme B, eliciting tumor cell apoptosis,⁵⁶ whereas Tremella fuciformis polysaccharides (TFPS) could specifically induce late-stage apoptosis in B16 cells by upregulating glucose transporter type 4 (GLUT4) and CD36, causing glucose/lipid metabolic dysregulation and cellular volumetric homeostasis collapse.⁴⁷ In all, these comprehensive modulations of apoptotic networks have underscored CHMPs' potential as multi-target therapeutic agents against melanoma.

2.3.3. Inhibiting tumor angiogenesis. In melanoma, the formation of new blood vessels is crucial for tumor growth and metastasis, as they provide essential oxygen and nutrients.⁵⁷ Thus, inhibition of tumor angiogenesis can offer a possible strategy to suppress the growth of tumor cells. Fucoidan was found to possess anti-angiogenic effects by restricting the blood supply to tumors, thereby inhibiting their growth and spread (Fig. 4).¹⁹ Vascular endothelial growth factor (VEGF) is a key angiogenic factor that promotes the formation of new blood vessels, supplying tumors with nutrients and oxygen. Inhibiting VEGF can thus block this process, slowing down the tumor growth and metastasis.¹⁴ Exopolysaccharides fraction of Cordyceps sinensis (EPSF) was shown to significantly reduce the expression levels of VEGF in the lung and liver tissues of tumor-bearing mice, suppressing the growth and metastasis of melanoma.¹⁴ And Ganoderma lucidum polysaccharides (GLP) were found to inhibit the expression levels of VEGF in B16-F10 cells.^58,59

Fig. 4 In vitro anti-angiogenic ability of fucoidan. (a) Experimental schedule of Chicken Embryo Chorioallantoic Membrane (CAM) experiment. (b) Intra-annular blood vessels at different concentrations of fucoidan. (c) Angiogenesis inside and outside the ring at 1000 μg mL⁻¹ of fucoidan. Adapted with permission from ref. 19. Copyright 2025 Elsevier.

2.3.4. Anti-melanoma metastasis. CHMPs can exert multi-target synergistic effects to suppress melanoma metastasis through systematic modulation of key steps in the metastatic cascade. Tumor invasion can be inhibited by CHMPs through regulation of extracellular matrix (ECM) degradation, a process that is critically dependent on matrix metalloproteinases (MMPs).⁶⁰ For instance, Cordyceps sinensis mycelia polysaccharides (CME) can significantly downregulate MMP1 overexpression in aggressive melanoma by inhibiting ERK/p38 MAPK signaling and stabilizing IκB-α,⁶¹ while Carthamus tinctorius polysaccharides (CTPS) can broadly suppress MMP3/7/9/10,⁶⁰ and carboxymethylated Saccharina cichorioides laminaran (ScLCM) can inhibit MMP9 activity in a concentration-dependent manner.³¹ Laminarin Sulfate (LAM) protects heparan sulfate proteoglycan (HSPG) integrity through heparinase (HPA) inhibition, blocking both ECM degradation and pro-metastatic factor release.¹⁷ These collective actions impair the invasive support provided by the tumor microenvironment, as exemplified by fucoxylomannan from Ganoderma lucidum (FXM),⁶² fucomannogalactan from Hypsizygus marmoreus (FMG-Hm),⁶³ and water-soluble glucan from Ganoderma lucidum (WSG),⁶⁴ all of which significantly suppress melanoma colony formation. Lee et al. demonstrated that red ginseng polysaccharides (RGAP) reduce lung metastases by 89% in mice.⁶⁵ Separately, Han et al. reported that Phellinus linteus polysaccharides (PL) can decrease B16F10 cell Matrigel invasion by 89%,⁶⁶ while Wu et al. confirmed that Agaricus bisporus cell-wall polysaccharides (Abwp) can downregulate metastasis-associated proteins (N-cadherin, MMP9, Snail).⁵³

Furthermore, CHMPs can disrupt integrin-mediated adhesion signaling. Intriguingly, Bupleurum chinense polysaccharides (BCP) can dose-dependently block β1 integrin binding to the fibronectin RGD motif (GST-FNIII9-11 domain) and selectively inhibit phosphorylation at FAK Tyr397 and paxillin Tyr118,⁶⁷ while Codonopsis lanceolata polysaccharides (CLPS) similarly interfere with the β1 integrin/FAK/paxillin axis to reduce B16F10 Transwell migration.⁶⁸ Both compounds specifically target integrin-dependent adhesion without affecting poly-L-lysine-mediated nonspecific adhesion. Additionally, CHMPs can modulate focal adhesion dynamics and cytoskeletal remodeling. For example, Bupleurum chinense polysaccharides (BCP) were experimentally confirmed to markedly reduce focal adhesion numbers and inhibit F-actin polymerization, thereby impairing cellular deformability and invasiveness.⁶⁷ Finally, CHMPs can reverse epithelial–mesenchymal transition (EMT) in melanoma cells. For example, water-soluble Glucan from Ganoderma lucidum (WSG) was found to convert cell morphology from filopodia-rich mesenchymal to rounded epithelial configurations through downregulation of mesenchymal markers (N-cadherin, Vimentin, Snail, Twist) and upregulation of epithelial markers (E-cadherin, γ-catenin), eventually strengthening intercellular junctions and inhibiting migration/invasion.⁶⁴

2.3.5. Antioxidant activity. Oxidative stress arises from free radical overproduction and compromised antioxidant defenses, inducing damage to DNA, proteins, and lipids that drives oncogenesis, including melanoma.⁶⁹ Notably, it activates tyrosinase (TYR) to accelerate melanin synthesis, a process now recognized as a key pathogenic factor in melanoma.⁷⁰ Through their antioxidant activity, CHMPs counteract these pathological mechanisms by scavenging free radicals and enhancing endogenous antioxidant capacity, directly impeding melanoma development. For instance, Ganoderma lucidum polysaccharides (GLP) were shown to reduce the production of ROS and mitigate mitochondrial damage, thereby decreasing intracellular oxidative stress.⁴⁵ Dioscorea opposita polysaccharides (CYS-2) were confirmed to exhibit strong antioxidant properties, including DPPH radical scavenging activity, ABTS⁺ radical scavenging activity, and hydroxyl radical scavenging activity.³⁵ Similarly, Bletilla striata polysaccharides (BSP) have demonstrated potent in vitro antioxidant activity, such as ABTS⁺ radical scavenging activity, ferric ion-reducing antioxidant power (FRAP), and oxygen radical absorbance capacity (ORAC).³⁸ Interestingly, Saussurea involucrata polysaccharides (SIP) also exhibit significant in vitro antioxidant capacity, effectively scavenging free radicals, including DPPH and ABTS radicals.⁴⁴ Additionally, strong DPPH radical scavenging ability and ferric ion reducing power have been demonstrated by enzymatically hydrolyzed Cuscuta chinensis polysaccharides (ECPS).³⁴

2.3.6. Inducing cell cycle arrest in melanoma cells. CHMPs have been demonstrated to suppress malignant melanoma proliferation through multi-stage cell cycle arrest by targeting critical regulatory nodes. At the G1/S transition checkpoint, Angelica sinensis polysaccharides (APS-4II) were found to block G1-to-S-phase progression, significantly increasing the proportion of G1-phase melanoma cells and delaying cycle progression.¹³ This G1-phase arrest mechanism was further linked to key regulatory proteins. Lycium barbarum active glycopeptides (LBAG) have been shown to induce G0/G1-phase arrest by suppressing Cyclin D1/CDK2 expression and upregulating p21,⁴⁹ whereas Agaricus bisporus cell-wall polysaccharides (Abwp)⁵³ and exopolysaccharides fraction of Cordyceps sinensis (EPSF)¹⁴ were shown to attenuate G1/S transition signals through downregulation of proto-oncogenes c-Myc and c-Fos. In the S-phase intervention, Sargassum fusiforme polysaccharides (SFPS) impaired DNA replication progression,¹¹ resulting in S-phase retention of B16F10 cells. Notably, PCNA-mediated arrest was confirmed to involve functional modulation of proliferating cell nuclear antigen (PCNA). Agaricus bisporus cell-wall polysaccharides (Abwp) have been demonstrated to impair PCNA-DNA polymerase complex formation, thereby reducing DNA synthesis efficiency.⁵³ Concerning G2/M-phase arrest, Zizyphus jujuba polysaccharides (DPP) have been shown to significantly increase the proportion of melanoma cells in G2/M-phase, confirming the induction of G2/M-phase arrest.⁵¹ Additionally, Lycopus lucidus polysaccharides (LLP) have been demonstrated to inhibit Cyclin B1 and CDK1 protein levels, which in turn induces G2/M-phase arrest.⁵⁰ Furthermore, Tremella fuciformis polysaccharides (TFPS) were found to interfere with spindle assembly checkpoint function, preventing mitotic completion and thus resulting in G2/M-phase arrest.⁴⁷

2.3.7. Regulating intestinal flora. CHMPs can also exert anti-melanoma effects by modulating the gut microbiota through multiple mechanisms, including regulating the structure of the gut microbiota, influencing the production of short-chain fatty acids (SCFAs), and modulating immune cell activity.³⁶ For instance, Panax ginseng polysaccharides (GP-n) have been reported to exert anti-melanoma effects by structural-specific modulation of gut microbiota and SCFA levels, demonstrating the most potent tumor-suppressive activity with a significant reduction in tumor weight.³⁶ Specifically, GP-n enriches beneficial gut bacteria (e.g., Allobaculum and Bifidobacterium genera) and restores anti-tumor SCFA levels (particularly acetate and butyrate).³⁶ Another example is Astragalus polysaccharides (APS), which have been evidenced to significantly modulate the composition of gut microbiota. Specifically, APS increases the abundance of beneficial bacteria such as Lactobacillus johnsonii and Faecalibaculum rodentium, alters the composition of fecal metabolites, and thereby leads to elevated levels of L-glutamate and creatine. These metabolites can further enhance the anti-tumor immune response of the body by influencing immune cell function, including boosting the activity of CD8⁺ T cells and reducing the activity of MDSCs.⁷¹ In another case, Ganoderma lucidum polysaccharides (GLP) were demonstrated to significantly modulate the composition and function of the gut microbiota by increasing the abundance of beneficial bacteria, such as Bacteroides, while reducing the abundance of harmful bacteria, such as Desulfovibrio. It was also shown to significantly reduce the Firmicutes-to-Bacteroidetes ratio.¹⁰ These changes can enhance T cell activity and promote macrophage polarization, thereby significantly inhibiting the growth and metastasis of melanoma.

2.3.8. Modulating the immune response. Early studies have shown that tumors grow more vigorously in immunodeficient or immunosuppressed animals, and cancer cells can express a variety of tumor-associated antigens that can be recognized by the immune system.⁷² However, spontaneous immune responses to these antigens are rarely sufficient to induce tumor regression. Therefore, activating and enhancing immune responses while eliminating immunosuppression is crucial for mounting an effective anti-tumor immune response. CHMPs can inhibit melanoma through a multi-layered immunomodulatory network encompassing comprehensive activation of innate immunity, specific amplification of adaptive immunity, and reversal and remodeling of the immunosuppressive microenvironment. As the command center of immune responses, DCs play a pivotal role in initiating antitumor immunity.⁷³ Neutral Lycium barbarum polysaccharides (NLBP) can induce the maturation of bone marrow-derived DCs via the TLR4-IKK-NF-κB signaling pathway, upregulating antigen presentation-related genes (e.g., CD40, CD80, CD86, CD205) and migration-related genes (e.g., L-selectin, CCR2, ICAM1), thereby establishing a functional chain from migration to antigen presentation.²⁵ Interestingly, Astragalus polysaccharides (APS) were found to enhance DC migration to lymph nodes by upregulating CCR7 expression while significantly elevating costimulatory molecules (CD40, CD80, CD86) and antigen-presenting molecules (MHC-I/II), constructing a multidimensional antigen-presentation network.⁹ In addition, Rehmannia glutinosa polysaccharides (RGP) can activate splenic DCs through a TLR4-dependent mechanism to secrete IL-12 and TNF-α, providing cytokine support for subsequent T cell differentiation.⁷³ Natural killer (NK) cells, innate cytotoxic effectors, recognize tumor surface anomalies for rapid killing.⁷⁴ Ganoderma lucidum polysaccharides (GLP) were shown to restore cytotoxicity by blocking αvβ3/α5β1 integrins to remove fibrinogen-mediated physical shielding,⁷⁵ while Astragalus polysaccharides (APS) directly activate NK cells to secrete perforin/granzyme B.⁹ Macrophages, the phagocytic immune cells that recognize and engulf tumor cells, have polarization states critically determining antitumor efficacy.⁷⁶ Angelica gigas polysaccharides (ISAg),⁷⁴ Tremella fuciformis polysaccharides (TFPS),⁷⁷ and Carthamus tinctorius polysaccharides (CTPS)⁶⁰ were reported to promote M1 polarization with elevated TNF-α, CD80, CD86, iNOS, IL-1β, and IL-12. Moreover, Ganoderma lucidum polysaccharides (GLP),¹⁰ Codonopsis pilosula polysaccharides (dCPP),¹⁶ and neutral Lycium barbarum polysaccharides (NLBP)²⁵ were demonstrated to shift M2 to M1 polarization, increasing M1/M2 ratios while upregulating M1 markers (IL-1β, IL-6, iNOS, TNF-α) and downregulating M2 markers (IL-4, Chil3, Retnla, Mrc1, Arg1, Fizz1). Interestingly, Rubus crataegifolius polysaccharides (RCP)⁷⁸ and Tremella fuciformis polysaccharides (TFPS)⁷⁷ were observed to enhance macrophage migration, phagocytosis, and proinflammatory mediator production (NO, TNF-α, IFN-γ), accompanied by upregulated iNOS/COX-2 expression.

In adaptive immunity, Ganoderma lucidum polysaccharides (GLP) upregulate melanoma cell MHC-I (H-2D^b/K^b) and CD80/CD86 to enhance CTL activation.⁷⁹ Honey-processed Astragalus polysaccharides (HP-APS) were observed to induce immunogenic cell death in B16 cells, releasing damage-associated molecular patterns (ATP, HSP70, CRT) to mature antigen-presenting cells and activate T cells.⁸⁰ Notably, Astragalus polysaccharides (APS) were confirmed to increase CD4⁺/CD8⁺ T cell infiltration and IFN-γ/TNF-α levels in melanoma-bearing mice.²³ Another example is Rehmannia glutinosa polysaccharides (RGP), which drives Th1/Tc1 differentiation via TLR4-dependent IL-12/TNF-α signaling.⁷³ Additionally, Tremella fuciformis polysaccharides (TFPS) promote Th17-derived IL-17/IFN-γ.⁸¹ B cells proliferate and secrete IgM under non-LPS stimulation by Angelica gigas pectic polysaccharides (Angelan),⁸² Rubus crataegifolius polysaccharides (RCP),⁷⁸ and Phellinus linteus polysaccharides (PL),⁶⁶ synergistically enhancing humoral immunity.

The immunosuppressive tumor microenvironment (TME), a hallmark of melanoma progression, involves checkpoint activation, inhibitory cytokine secretion, and immune cell exhaustion.²⁴ Notably, Astragalus polysaccharides (APS) were found to downregulate PD-L1 in melanoma stem cells (MSCs) via PI3K/AKT inhibition, restoring CD4⁺/CD8⁺ T cell infiltration and IFN-γ/TNF-α secretion while reducing MSC sphere formation and stemness markers (CD133, OCT4, Nanog, BMI, ALDH1A3, SOX2, CD47).^23,83,84 Additionally, Ganoderma lucidum polysaccharides (GLP) and Astragalus polysaccharides (APS) can counteract immunosuppressive factors (IL-10, TGF-β, VEGF, Arg-1) that inhibit lymphocyte proliferation and macrophage phagocytosis.^{56,58,59,71,79} Remarkably, ginseng berry polysaccharides (GBPP)¹⁵ and Astragalus polysaccharides (APS)⁹ were found to synergistically activate multiple immune cell populations, including DCs, NK cells, and T cells, leading to substantial increases in pro-inflammatory cytokines (IL-6, IL-12, TNF-α, IFN-γ) and cytotoxic mediators (granzyme B, perforin) within the TME.

2.3.9. Regulating signaling pathways. Melanoma's pronounced heterogeneity and therapy resistance are mechanistically linked to aberrant activation of interconnected signaling networks. CHMPs were demonstrated to overcome these challenges through coordinated modulation of core signaling axes—including but not limited to TLR4/NF-κB, MAPK, and PI3K/Akt pathways—which collectively activate anti-tumor immunity, suppress tumor proliferation/metastasis, and reprogram the immunosuppressive tumor microenvironment (TME), thereby establishing a novel polypharmacological paradigm to address current therapeutic limitations. Regarding innate immune activation, neutral Lycium barbarum polysaccharides (NLBP) were found to promote DC maturation and antigen presentation via the TLR4-IKK-NF-κB axis,²⁵ while Angelica gigas polysaccharides (ISAg), acting through the TLR4-MyD88 cascade, can activate macrophages and DCs to secrete IL-12.⁷⁴ Furthermore, this interleukin was shown to enhance NK cells’ cytotoxicity via upregulated perforin, TRAIL, and FasL expression. In parallel, Tremella fuciformis polysaccharides (TFPS) were reported to drive M1 macrophage polarization through concurrent MAPK/NF-κB activation, resulting in robust production of pro-inflammatory mediators such as NO, TNF-α, and IL-6.⁷⁷ For direct tumoricidal effects, Sargassum fusiforme polysaccharides (SFPS) were observed to induce apoptosis via PI3K/Akt/Bcl-2 pathway inhibition.¹¹ Similarly, Lycium barbarum active glycopeptides (LBAG) triggered dual cell cycle arrest and apoptosis through ROS-dependent P38-MAPK activation coupled with AKT suppression,⁴⁹ whereas carboxymethylated Saccharina cichorioides laminaran (ScLCM) can impair melanoma proliferation and invasion by inhibiting ERK/MAPK signaling.³¹ In terms of TME reprogramming, water-soluble glucan from Ganoderma lucidum (WSG) was demonstrated to suppress metastasis by downregulating MMP1 expression through TGF-β pathway inhibition.⁶⁴ More significantly, Agaricus bisporus cell-wall polysaccharides (Abwp) can reverse tumor stemness by blocking NF-κB-p65 nuclear translocation and restoring c-Myc/p53 balance via p38-MAPK/NF-κB crosstalk.⁵³ Interestingly, Dioscorea batatas polysaccharides (DsCE)⁸⁵ and Cordyceps sinensis mycelia polysaccharides (CME)⁶¹ were shown to differentially regulate immune responses and metastasis-associated molecules through p38-MAPK/NF-κB and ERK pathway modulation, respectively. This multi-pathway synergistic approach not only inhibits oncogenic signaling cascades but, more importantly, reprograms the tumor-immune interaction network, thereby establishing an innovative strategy to overcome melanoma drug resistance.

3. CHMPs combined with other drugs for melanoma therapy

CHMPs have been shown to exhibit multi-target synergistic effects in combined antitumor therapy. They exert direct antitumor activity by inducing tumor cell apoptosis and inhibiting tumor angiogenesis.⁵⁶ Furthermore, they have been demonstrated to enhance systemic immune responses through DCs activation and the promotion of NK cells’ cytotoxicity.⁸⁶ Additionally, these polysaccharides have been shown to coordinately regulate immunosuppressive and immunostimulatory factors to remodel the tumor microenvironment.⁵⁹ Clinical studies have confirmed that Astragalus polysaccharides (APS)⁸⁷ and Lentinan (LNT),⁸⁸ when combined with chemotherapy, could prolong patient survival and improve quality of life. Therefore, CHMPs can also be used in combination with other drugs in melanoma therapy with enhanced therapeutic efficacy. For instance, Cordyceps cicadae polysaccharides (CCPa) have been reported to synergize with cisplatin to inhibit the proliferation and metastasis of B16-F10 cells.⁸⁹ The synergistic effect of red ginseng polysaccharides (RGAP) with rIFN-γ activates NF-κB in macrophages, enhancing its DNA-binding ability and P65 protein expression. This promotes the production of cytokines (IL-1, IL-6, TNF-α, and NO) and increases the ability to kill B16 tumor cells.⁹⁰ Combined treatment with Angelica gigas pectic polysaccharides (Angelan) and doxorubicin can significantly inhibits tumor growth and improves survival rates in mice.⁸² Astragalus polysaccharides (APS) were confirmed to reduce stem-like properties in melanoma, enhancing their sensitivity to chemotherapeutic agents. When combined with cisplatin, APS can significantly suppress tumor growth.⁸⁴ Interestingly, honey-processed Astragalus polysaccharides (HP-APS) exhibit stronger anti-tumor effects when used in combination with PD-1 antibodies.⁸⁰ After intranasal administration of Astragalus polysaccharides (APS), the anti-cancer effects of anti-PD-L1 antibodies were enhanced, which significantly prolonged the survival of mice with lung metastatic melanoma. This effect is dependent on the involvement of NK cells and CD8⁺ T cells, supporting APS as a potential immunostimulant that can be combined with immune checkpoint inhibitors to improve therapeutic outcomes.⁹

CHMPs can also serve as vaccine adjuvants to enhance vaccine efficacy. They primarily enhance immune responses, prolong antigen presentation, promote antigen processing and presentation, modulate immune types, reduce antigen doses, and broaden protective coverage.⁷³ For instance, Dioscorea batatas polysaccharides (DsCE) were shown to enhance the immunogenicity of hgp100 DNA vaccines by modulating NF-κB activation levels, thereby improving the protective effect of the vaccine against B16-hgp100 melanoma.⁸⁵ As an adjuvant for ovalbumin (OVA), Rehmannia glutinosa polysaccharides (RGP) have been demonstrated to promote DC maturation and OVA-specific immune activation, inhibiting tumor growth in a TLR4-dependent manner.⁷³ Similarly, RGP can act as an adjuvant for tyrosinase-related protein 2 (TRP2), primarily by promoting DCs maturation, activating Th1-type immune responses, enhancing TRP2-specific T cell responses, and increasing CTL activity, thereby inhibiting melanoma growth.⁸⁶

4. CHMPs used as drug-carriers for melanoma therapy

The intrinsic anti-tumor activity of CHMPs has enabled their outstanding capability of being carrier-free agents in melanoma treatment. On the other hand, as natural biomaterials, CHMPs have been designed and fabricated into various drug delivery systems thanks to state-of-the-art molecular engineering. Due to their excellent bioactivity, biocompatibility, and biodegradability, CHMPs have been engineered into multifunctional platforms, including nanoparticles,¹⁷ nanovaccines,¹⁸ microneedles,¹⁹ and hydrogels⁴ (Table 1). These intelligent systems not only enhance drug bioavailability but also exert inherent anti-tumor effects via tumor microenvironment-responsive drug release. In particular, their inherent targeting properties minimize off-target toxicity while improving payload accumulation in melanoma lesions, achieving dual optimization of therapeutic efficacy and treatment safety.

Table 1 CHMP-based drug delivery systems

Name	Type	Vehicle	Drug	Preparation Methods	Ref.
DOX-nPLPs	Nanoparticle	Laminarin sulfate (LAM)	Doxorubicin (DOX)	Esterification reaction; ultrasonic emulsification; solvent evaporation; dialysis; nanoprecipitation	17
Se-Len	Nanoparticle	Lentinan (LNT)	Selenium (Se)	Acid activation reaction; selenation reaction; neutralization and purification; dialysis	92
PNP-PEI/shPD-L1	Nanoparticle	Panax notoginseng polysaccharides (PNPs)	Short hairpin RNA targeting PD-L1 (shPD-L1)	Oxidation treatment; Schiff base reaction and PEI grafting; electrostatic interactions	93
CLNTO	Nanovaccine	Lentinan (LNT)	OVA	Carboxylation reaction; activation reaction; amidation reaction; self-assembly reaction	18
APS-NVs	Nanovaccine	Astragalus polysaccharides (APSs)	OVA257-264	Microfluidic method; self-assembly reaction; surface precipitation method	32
Cu-Apa/HA-Chol@APS-Gel	Hydrogel	Astragalus polysaccharides (APSs)	Cu-Apa/HA-Chol	Oxidation reaction; coordination reaction; esterification reaction; self-assembly reaction; Schiff base reaction	96
MnP@DOP-Gel	Hydrogel	Dendrobium officinale polysaccharides (DOPs)	The pectin/Mn^2+ microspheres	Emulsion-solvent diffusion method; coordination reaction; borate ester crosslinking reaction	4
TF-MNs	Microneedle	Fucoidan	Tellurium nanoparticles (Te NPs)	Reduction of Te^4+ ions; plasticity of PDMS microneedle molds	19
MNs-WSG	Microneedle	Polyvinyl alcohol (PVA); polyvinylpyrrolidone (PVP)	Water-soluble glucan from Ganoderma lucidum (WSG)	Plasticity of PDMS microneedle molds	64
Cur-HMP/ZIF-8@DOX-PNP/AS-HMP MNs	Microneedle	Panax notoginseng polysaccharides (PNPs)	ZIF-8@DOX	One-pot method; three-step casting process	99

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4.1. Nanoparticles

Nanoparticles have been widely employed in drug delivery, targeted therapy, and gene therapy due to their unique properties, including high surface-area-to-volume ratios, size effects, and surface modifiability.⁹¹ Recently, CHMPs have emerged as ideal materials for constructing multifunctional nanoparticle systems due to their antitumor activity, biocompatibility, and structural tailorability. Several CHMP-based nanoparticle systems have been designed via structure-function synergy and have demonstrated distinct therapeutic mechanisms and advantages, enabling multidimensional melanoma therapy. Liu et al. designed a targeted organic selenium complex Se-len by covalently linking inorganic selenium to the Lentinan (LNT) backbone via selenoether bonds (–O–Se–).⁹² Unlike inorganic selenium (e.g., sodium selenite), Se-len not only delivers selenium selectively to tumor tissues but also suppresses tumor invasion and metastasis by inhibiting epithelial–mesenchymal transition (EMT).⁹² In another study, Ma et al. pioneered the synthesis of cationic Panax notoginseng polysaccharide (PNP)-polyethyleneimine (PEI) copolymers by initially oxidizing PNP with periodate to generate aldehyde functionalities, subsequently grafting PEI through Schiff base conjugation.⁹¹ Such cationic PNP-PEI carriers can electrostatically interact with anionic exogenous shPD-L1 nucleic acids to form self-assembled nanoparticles.⁹¹ This PNP-PEI/shPD-L1 system represents an innovative immune checkpoint-modulated gene delivery platform, where PNP-PEI/shPD-L1 nanoparticles can efficiently deliver shPD-L1 into B16-F10 cells, specifically downregulating PD-L1 expression via RNA interference to alleviate immune checkpoint suppression, thereby enhancing immune-mediated tumor recognition and attack. Moreover, PNP-PEI/shPD-L1 nanoparticles can reprogram the tumor immune microenvironment by polarizing M2 macrophages toward the M1 phenotype, increasing the IL-12/IL-10 secretion ratio, and promoting DC maturation (evidenced by elevated CD86⁺ and CD11c⁺ populations), which activates T cell-mediated antitumor immunity.⁹³ Another ROS-responsive nanoparticle (DOX-nPLPs) loaded with doxorubicin (DOX) has been developed by Zhang et al. through co-assembly of polypropylene sulfide (PPS), laminarin sulfate (LAM), and polyethylene glycol (PEG).¹⁷ Here, LAM synergizes with DOX to inhibit metastasis, while PPS confers ROS-responsive drug release properties. In the high-ROS tumor microenvironment, oxidation converts the hydrophobic PPS backbone into hydrophilic sulfoxides, triggering nanoparticle disintegration and DOX release.¹⁷ Experiments have confirmed that DOX-nPLPs can enhance DOX uptake in B16F10 cells in an H₂O₂-dependent manner. Specifically, they can significantly downregulate the expression of heparinase (HPA) and Ki-67, promote apoptosis, and inhibit cell migration and invasion. In vivo imaging further validated their tumor-targeting efficacy toward primary and metastatic lesions without off-target organ toxicity.¹⁷ Collectively, these nanoparticle systems with mechanisms of targeting metastasis-inhibiting pathways, immune checkpoint blockade, and microenvironment-triggered drug release, would provide a multifaceted strategy for precision melanoma therapy, highlighting the vast potential of CHMP-based nanoparticles in functionalized nanomedicine design.

4.2. Nanovaccines

Nanovaccines have demonstrated enhanced antigen delivery efficiency and potentiated immune response magnitude through a strategic integration of nanotechnology with immunoadjuvant functions.⁹⁴ A notable example is the Astragalus polysaccharide (APS)-based self-adjuvanting nanovaccine (APS-NVs), where microfluidic technology facilitates the co-assembly of model antigen OVA_257–264 with APS, subsequently encapsulated within a calcium phosphate (CaP) core–shell structure.³² The prepared APS-NVs exhibit good stability, including physicochemical, storage, and functional stability. In vitro studies revealed that APS-NVs can significantly improve DC antigen uptake efficiency and promote CD8⁺ T cell activation via cross-presentation. Mechanistically, APS activates DC surface receptors (TLR4, TLR2, and dectin-1), inducing DC maturation characterized by upregulated expression of co-stimulatory molecules (CD80/CD86) and antigen-presenting molecules (MHC-II), along with enhanced secretion of pro-inflammatory cytokines including IL-12p70 and IFN-γ.³² In B16-OVA melanoma models, APS-NVs exhibited superior lymph node targeting capability following subcutaneous administration, rapidly accumulating in draining lymph nodes to promote DC maturation and T cell activation, ultimately achieving significantly better tumor suppression than conventional aluminum adjuvants.³² In another case, Yu et al. have engineered cation-modified lentinan (CLNT) through PEI conjugation, enabling electrostatic self-assembly with OVA to form a CLNTO nanovaccine, which exhibits good stability, including physical and chemical stability, storage stability, physiological stability, and functional stability.¹⁸ The CLNTO system not only protects antigens from degradation but also facilitates lysosomal escape (Fig. 5a) and antigen cross-presentation (Fig. 5b) via TLR2/4-mediated signaling pathways.¹⁸ This nanovaccine demonstrates efficient lymph node-targeted delivery, significantly enhancing germinal center (GC) reactions while promoting T follicular helper (Tfh) cell differentiation and memory B cell formation, accompanied by elevated serum OVA-specific IgG levels.¹⁸ In B16-OVA models, CLNTO treatment groups show markedly improved tumor suppression compared to Alum controls, without inducing systemic toxicity. The system further prolongs antigen persistence in vivo through controlled release kinetics, while simultaneously activating both CD8⁺ and CD4⁺ T cell populations to reinforce cellular and humoral immunity.¹⁸ Collectively, CHMPs were found to serve as dual-functional nanovaccine platforms that combine antigen delivery with intrinsic immunoadjuvant properties. Through targeted delivery and receptor-mediated immunomodulation, these systems can efficiently activate antigen-specific T-cell responses, offering a promising strategy for cancer immunotherapy that balances high efficacy with favorable safety profiles.

Fig. 5 (a) Confocal laser scanning microscopy (CLSM) images of nanovaccine-treated BMDCs with OVA-FITC in green, nuclei in blue (DAPI), and lysosomes in red (Lyso-Tracker). Scale bar: 10 μm. (b) A schematic illustrating that CLNTO nanovaccines enhance intracellular OVA uptake, antigen cross-presentation, and BMDC activation via TLR2 and TLR4 receptors. Adapted with permission from ref. 18. Copyright 2024 Wiley.

4.3. Hydrogels

Hydrogels, characterized by their three-dimensional hydrophilic polymeric networks, have emerged as transformative platforms in drug delivery and tumor therapy due to their unique combination of biocompatibility, controlled biodegradation, and tunable drug release profiles.⁹⁵ Beyond providing structural integrity through their macromolecular architectures, CHMPs have exhibited dual functionality by conferring intrinsic bioactive properties such as antioxidant and immunomodulatory activities, thereby enabling the development of innovative structure-function integrated hydrogel systems. Kang et al. reported a hydrogel based on Astragalus polysaccharides (APSs), fabricated via periodate-mediated oxidation to introduce aldehyde groups onto APS. Subsequently, Schiff base crosslinking was performed with the amino groups of carboxymethyl chitosan, ultimately resulting in a porous three-dimensional network.⁹⁷ This thermoresponsive hydrogel exhibits rapid gelation (77 s at 37 °C) and sustained degradation characteristics (62% over 16 days), with its porous architecture enabling efficient encapsulation of Cu-Apa/HA-Chol composite micelles to form the Cu-Apa/HA-Chol@APS-Gel delivery system.⁹⁶ Experimental results have demonstrated that the synergistic action of Cu²⁺ and Apatinib (Apa) can significantly inhibit vasculogenic mimicry (VM), as evidenced by reduced tube formation (both in number and length) by B16-F10 cells.⁹⁶ The APS-Gel further enhances anti-VM efficacy through its dual mechanism of sustained drug release and targeted delivery, achieving superior therapeutic outcomes compared to free drug administration. For postoperative applications, Gao et al. engineered a ROS-responsive MnP@DOP-Gel through dynamic borate ester crosslinking (Fig. 6a and b), and manganese-pectin microspheres (MnP) were incorporated (Fig. 6c).⁴ The boronic ester crosslinked network in DOP-Gel undergoes oxidative cleavage under high-concentration H₂O₂ conditions, resulting in boronate bond degradation. This leads to hydrogel network disintegration and subsequent release of encapsulated MnP microspheres. This innovative design has leveraged DOP's antioxidant capacity to mitigate oxidative stress while MnP releases Mn²⁺ in response to the ROS levels of the tumor microenvironment, activating the cGAS-STING pathway to induce IRF3 phosphorylation and IFN-1β production (Fig. 6d).⁴ The resultant immunogenic cell death (ICD), coupled with M1 macrophage polarization and DC maturation, establishes a robust antitumor immune cascade, all achieved with localized Mn²⁺ delivery that minimizes systemic neurotoxicity risks.⁴ All these findings have illustrated the versatile roles of CHMPs in hydrogel design, wherein they can provide structural support, deliver bioactive functions, and enable controlled release of drugs. This integration of natural biomacromolecules with advanced material technologies offers a promising approach to develop innovative cancer therapies.

Fig. 6 (a) Schematic illustration of MnP@DOP-Gel preparation. (b) SEM image of DOP-Gel. Scale bar: 10 μm. (c) Confocal image of MnP@DOP-Gel (MnPs labeled by Nile red). Scale bar: 200 μm. (d) Illustration of MnP@DOP-Gel combined with anti-PD-1 antibody for mediating T cell killing. Adapted with permission from ref. 4. Copyright 2024 Ivyspring.

4.4. Microneedles

Microneedles (MNs) have emerged as a promising platform for localized melanoma therapy, leveraging their painless transdermal delivery, high drug-loading capacity, and controlled release properties.⁹⁷ By penetrating the stratum corneum to deliver therapeutics directly to lesion sites, MNs can overcome the systemic toxicity and poor targeting limitations of conventional chemotherapy while enabling multimodal combination strategies integrating photothermal therapy, chemotherapy, and anti-angiogenesis for enhanced efficacy.⁹⁸ CHMPs can serve as ideal bioactive building blocks for fabricating MNs due to their natural origin, biocompatibility, and multifunctional properties (e.g., antitumor, immunomodulatory, and tissue-repair activities). Lo et al. fabricated glucan patch-based MNs by injecting a mixture of water-soluble glucan from Ganoderma lucidum (WSG), polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP) into polydimethylsiloxane (PDMS) molds, followed by curing and demolding. Such MNs have exhibited strong mechanical strength (>10¹⁰ Pa) that exceeds skin penetration thresholds (10⁷ Pa) while achieving 70% sustained WSG release.⁶⁴ This MN system can significantly suppress the migration/invasion of melanoma cells by downregulating TGFβ receptors (TGFβR-I/II), inhibiting Smad2/ERK phosphorylation, and reducing EMT transcription factors (Snail/Twist).⁶⁴ In another study, Ye et al. constructed a soluble microneedle system (TF-MNs) for combined photothermal-antiangiogenic therapy through loading tellurium nanoparticles (Te NPs) and fucoidan into a polycaprolactone (PCL)-based matrix, followed by PDMS mold filling and room-temperature curing (Fig. 7a).¹⁹ The Te NPs demonstrated exceptional photothermal conversion efficiency under 808 nm near-infrared (NIR) irradiation, enabling direct tumor cell ablation through localized hyperthermia (Fig. 7b).¹⁹ Meanwhile, fucoidan can effectively suppress endothelial cell migration and tube formation, thereby inhibiting tumor angiogenesis (Fig. 7c). This synergistic combination resulted in a 5–10% enhancement in tumor suppression efficacy in vivo compared to monotherapy groups, as demonstrated in animal studies.¹⁹ To address postoperative recovery needs, Hu et al. prepared a dual-layer microneedle patch (Cur-HMP/ZIF-8@DOX-PNP/AS-HMP MNs) with a three-tiered functional architecture by using zwitterionic polymer SBMA (poly(sulfobetaine methacrylate)) (Fig. 8).⁹⁹ The rapidly dissolving layer (ZIF-8@DOX/PNP) can respond to the tumor's acidic microenvironment to release doxorubicin (DOX), where Panax notoginseng polysaccharides (PNP) serve as both a drug carrier and biocompatibility enhancer, facilitating drug transport while potentially mitigating immune rejection and inflammatory responses. The photothermal layer (HMP/Cur) achieves rapid temperature elevation to 56.5 °C within 60 seconds under near-infrared (NIR) irradiation, synergistically enhancing chemotherapeutic drug penetration and efficacy. The foundational healing layer (AS/HMP) accelerates wound closure through stimulated collagen deposition, completing this integrated therapeutic approach.⁹⁹ These functionalized MN systems have exemplified integrated multimodal melanoma therapy and postoperative recovery. Future efforts should optimize drug-loading ratios, stimulus-responsive release kinetics (e.g., pH/temperature), and scalable manufacturing to accelerate clinical translation toward safer/more effective melanoma treatments.

Fig. 7 (a) Composition, fabrication, and application of tellurium nanoparticle and fucoidan-loaded dissolvable microneedles in combined photothermal therapy and anti-angiogenesis for melanoma treatment. (b) Photothermal therapy for tumors mediated by tellurium nanoparticles. (c) Anti-angiogenic effects of fucoidan in tumor therapy. Adapted with permission from ref. 19. Copyright 2025 Elsevier.

Fig. 8 (a) Preparation and combined chemo-photothermal therapy for melanoma of Cur-HMP/ZIF-8@DOX-PNP/AS-HMP microneedle patches. (b) Photograph of Cur-HMP/ZIF-8@DOX-PNP/AS-HMP MN patch. (c) The bright-field micrograph of the single double-layered tip. Scale bar: 500 μm. Microneedle height: 1000 μm. (d) SEM image of Cur-HMP/ZIF-8@DOX-PNPS/AS-HMP MNs. Scale bar: 1 mm. Adapted with permission from ref. 99 Copyright 2025 Elsevier.

5. Conclusions

In summary, CHMPs have been recognized as strategic candidates for anti-melanoma drug development due to their natural abundance, structural diversity, biosafety, and potent antitumor activity. This review systematically highlights the dual roles of CHMPs in melanoma therapy, functioning both as multi-mechanistic therapeutic agents and engineerable drug carriers. Substantial evidence has demonstrated that CHMPs mediate direct therapeutic effects through immunomodulation, apoptosis induction, and metastasis suppression. Critically, these multifaceted therapeutic mechanisms can be spatially and temporally enhanced through CHMPs' intrinsic structural versatility, which enables their engineering into smart delivery systems (e.g., microneedles, hydrogels). This integrated “therapeutic-delivery” paradigm not only preserves the multicomponent synergy characteristic of traditional Chinese medicine but also provides innovative solutions for precision oncology. The established clinical use of specific CHMPs, such as Astragalus polysaccharides in China for lung cancer support¹⁰⁰ and Lentinan in Japan as a gastric cancer adjuvant,¹⁰¹ provides strong translational precedent for their application in melanoma, particularly given their shared immunomodulatory mechanisms relevant to enhancing melanoma treatment outcomes.

Despite significant research progress of CHMPs in anti-melanoma therapy, many challenges are still present and should be carefully addressed to further promote the real clinical applications of CHMPs. First, current structure–activity relationship studies remain largely confined to primary structural features (monosaccharide composition and glycosidic bonds), whereas the regulatory mechanisms of higher-order structures (e.g., triple-helix conformations and supramolecular assemblies) on bioactivity are yet to be elucidated. Key techniques like small-angle X-ray scattering (SAXS),¹⁰² cryo-electron microscopy (cryo-EM),¹⁰³ low temperature scanning tunneling microscopy (LT-STM),¹⁰⁴ atomic force microscopy (AFM),¹⁰⁵ and solid-state nuclear magnetic resonance (NMR)¹⁰⁶ are crucial for characterizing the higher-order structures of polysaccharides. Moreover, integrating molecular dynamics (MD) simulations,¹⁰⁷ surface plasmon resonance (SPR),¹⁰⁸ and fluorescence resonance energy transfer (FRET)¹⁰⁹ can offer deeper insights into CHMPs' structure–activity relationships. Second, the biological complexity of human melanoma, characterized by both intratumoral genetic heterogeneity and spatially organized immune microenvironments, cannot be fully recapitulated by conventional models (e.g., A375/B16 cell lines or xenografts). Therefore, the anti-melanoma efficacy of CHMPs should be systematically validated in advanced model systems, particularly patient-derived organoids (PDOs), which retain the genetic and phenotypic heterogeneity of primary tumors. A multi-region PDO library, constructed through sampling of distinct anatomical regions from the same tumor, would enable precise evaluation of CHMPs against driver-mutated and drug-resistant subpopulations. To bridge the gap between preclinical models and human trials, the development of humanized melanoma models with functional immune systems (e.g., NSG-SGM3 mice engrafted with patient-matched immune cells) is strongly recommended. Last but not least, despite their notable antitumor activity and potential as smart delivery platforms, CHMPs encounter challenges in clinical translation, primarily stemming from structural heterogeneity—a double-edged sword that endows them with diverse pharmacological activities yet jeopardizes the stability of efficacy. To address these issues, saccharide mapping might be used to analyze and distinguish the structural heterogeneity of CHMPs.¹¹⁰ Multi-omics investigations can also be used to elucidate molecular-level structure–function relationships, advancing quality control paradigms and efficacy evaluation.¹¹¹

For CHMP-based carrier systems, their inherent hydrophilicity imposes significant limitations on loading hydrophobic drugs, resulting in suboptimal encapsulation efficiency and payload capacity. To overcome this limitation, strategic grafting of hydrophobic moieties, such as fatty acid chains, onto polysaccharide backbones, generating amphiphilic derivatives, can be employed. The resulting architectures would facilitate hydrophobic drug–carrier interactions via micellar core formation, significantly enhancing both drug-loading efficiency and encapsulation efficacy. To further optimize tumor-specific delivery, stimuli-responsive design strategies can be implemented. For example, pH-sensitive carboxymethyl groups would endow the system with responsiveness to the acidic tumor microenvironment (pH 6.5–7.0),¹¹² while intracellular glutathione (GSH)-responsive disulfide linkages would enable precise spatiotemporal drug release.¹¹³ These structural modifications to CHMPs are assumed to not only improve the drug delivery efficiency of polysaccharide-based carriers but also enhance their therapeutic potential in tumor treatment.

In all, CHMPs can serve as both therapeutic agents and drug carriers, a dual functionality unattainable with conventional synthetic platforms. The abundance and excellent bioactivity of CHMPs will offer significant opportunities for researchers to develop these natural macromolecules into first-in-class melanoma or even other tumor therapeutics that harmonize Eastern and Western medical paradigms.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the SI. The Supplementary Information file contains a comprehensive summary of the literature reviewed in the manuscript. See DOI: https://doi.org/10.1039/d5tb01185j

Acknowledgements

This work was supported by the Key Projects in the Field of Traditional Chinese Medicine under the Tianjin Municipal Health Commission (2025006), Science and Technology Innovation Project of China Academy of Chinese Medical Sciences (CI2021A04903), and the National Key R&D Program of China (2023YFC3504101).

References

1. G. V. Long, S. M. Swetter, A. M. Menzies, J. E. Gershenwald and R. A. Scolyer, Lancet, 2023, 402, 485–502.
2. J. Huang, S. C. Chan, S. Ko, V. Lok, L. Zhang, X. Lin, D. E. Lucero-Prisno III, W. Xu, Z. Zheng, E. Elcarte, M. Withers and M. C. S. Wong, Am. J. Clin. Dermatol., 2023, 24, 965–975.
3. M. Arnold, D. Singh, M. Laversanne, J. Vignat, S. Vaccarella, F. Meheus, A. E. Cust, E. de Vries, D. C. Whiteman and F. Bray, JAMA Dermatol., 2022, 158, 495–503.
4. N. Gao, Y. Huang, S. Jing, M. Zhang, E. Liu, L. Qiu, J. Huang, B. Muhitdinov and Y. Huang, Theranostics, 2024, 14, 3810–3826.
5. J. N. Sanchez, T. Wang and M. S. Cohen, Drugs, 2018, 78, 549–566.
6. T. K. Eigentler, J. C. Hassel, C. Berking, J. Aberle, O. Bachmann, V. Grünwald, K. C. Kähler, C. Loquai, N. Reinmuth, M. Steins, L. Zimmer, A. Sendl and R. Gutzmer, Cancer Treat. Rev., 2016, 45, 7–18.
7. S. Bouchereau, L. Chaplain, M. Fort, A. Beauchet, T. Sidibé, M. Chapalain, L. Gonzalez-Lara, C. Longvert, A. Blom, P. Saiag and E. Funck-Brentano, Br. J. Cancer, 2021, 125, 948–954.
8. H. Xue, P. Li, J. Bian, Y. Gao, Y. Sang and J. Tan, Front. Nutr., 2022, 9, 1005181.
9. J. Hwang, W. Zhang, Y. Dhananjay, E. An, M. Kwak, S. You, P. C. Lee and J. Jin, Int. J. Biol. Macromol., 2021, 182, 1292–1300.
10. H. Xian, J. Li, Y. Zhang, D. Li, Y. Zhu, S. Li, Z. Tan, Z. Lin, X. Li and Y. Pan, Front. Pharmacol., 2021, 12, 650216.
11. F. Xu, H. Ding, Z. Liu, X. Jiang, Y. Ma, D. Wang and S. Xu, Mol. Biol. Rep., 2023, 50, 6517–6528.
12. Q. Zhou, S. Xiao, R. Lin, C. Li, Z. Chen, Y. Chen, C. Luo, Z. Mo and Y. Lin, Chin. J. Integr. Med., 2024, 30, 52–61.
13. T. Zhang, W. Liu, C. Fu, Y. Qiao, K. Xiao, L. Ren, C. Feng, J. Wang, W. Yang, X. Li and W. Cao, Int. J. Biol. Macromol., 2021, 183, 972–981.
14. J. Yang, W. Zhang, P. Shi, J. Chen, X. Han and Y. Wang, Pathol., Res. Pract., 2005, 201, 745–750.
15. D. Lee, C. W. Park, S. J. Lee, H. Park, S. H. Kim, S. Son, J. Park and K. Shin, Front. Pharmacol., 2019, 10, 1411.
16. H. Liu, W. K. Amakye and J. Ren, Biomed. Pharmacother., 2021, 142, 112016.
17. Y. Zhang, Y. Li, S. Huang, H. Zhang, Q. Lin, T. Gong, X. Sun, Z. Zhang and L. Zhang, Nanoscale, 2021, 13, 15267–15277.
18. R. Yu, L. Jin, Z. Song, L. Jiao, Z. Wang, Y. Zhou, Y. Ma, S. Guan, Z. Zhang, D. Wang, H. Liu, Y. Sun, S. Zhang, T. Cai, H. Sun, Y. Qiu, J. Miao and Z. Liu, Small, 2024, 20, 2402792.
19. Z. Ye, Y. Li, Y. Sun, H. Ye, J. Tang, G. Cao, Z. Feng, Y. Bao, Y. Zeng, Z. Pan, X. Liu and Y. He, Int. J. Biol. Macromol., 2025, 292, 139153.
20. P. B. S. Albuquerque, W. F. de Oliveira, P. M. Dos Santos Silva, M. T. Dos Santos Correia, J. F. Kennedy and L. C. B. B. Coelho, Carbohydr. Polym., 2022, 277, 118824.
21. X. Huang, S. Li, R. Ding, Y. Li, C. Li and R. Gu, Int. J. Biol. Macromol., 2023, 252, 126313.
22. L. Tu, B. Xing, S. Ma, Z. Zou, S. Wang, J. Feng, M. Cheng and Y. Jin, Int. J. Biol. Macromol., 2025, 304, 140820.
23. H. Yu, G. Ding, Q. Gong, J. Ma, Y. Zhao, Y. Wang, X. Qiao and X. Cheng, BMC Cancer, 2024, 24, 1034.
24. X. Li, Z. Wang, Y. Zhao, S. Luo, D. Zhang, S. Xiao and Z. Peng, Carbohydr. Polym., 2012, 89, 942–947.
25. J. Duan, M. Liu, Y. Liu, X. Liang, C. Cao, A. Yao, L. Zhao, S. Guo, D. Qian, C. Bao, M. Zhao and J. Duan, Biomed. Pharmacother., 2024, 181, 117659.
26. M. O. Elnahas, W. A. Elkhateeb and G. M. Daba, Int. J. Biol. Macromol., 2024, 266, 130893.
27. Y. Ying and W. Hao, Front. Immunol., 2023, 14, 1147641.
28. G. Chen, Y. Fu, W. Yang, Q. Hu and L. Zhao, Int. J. Biol. Macromol., 2017, 107, 2150–2156.
29. C. Wang, C. Lu, Y. Hsueh, W. Liu and C. Chen, Appl. Microbiol. Biotechnol., 2014, 98, 9389–9398.
30. H. Wang, R. Hunter, Q. Zhang, H. Yu, J. Wang, Y. Yue, L. Geng and N. Wu, Carbohydr. Polym., 2024, 342, 122407.
31. O. S. Malyarenko, R. V. Usoltseva, A. B. Rasin and S. P. Ermakova, Int. J. Biol. Macromol., 2023, 226, 803–812.
32. N. Li, Y. Zhang, M. Han, T. Liu, J. Wu, Y. Xiong, Y. Fan, F. Ye, B. Jin, Y. Zhang, G. Sun, X. Sun and Z. Dong, Sci. China: Life Sci., 2024, 67, 680–697.
33. C. Dong, L. Liu, C. Wang, Z. Fu, Y. Zhang, X. Hou, C. Peng, R. Ran and Z. Yao, Int. J. Biol. Macromol., 2018, 113, 748–756.
34. Z. Liu, Y. Wang, Q. Li and L. Yang, Braz. J. Med. Biol. Res., 2018, 51, 1–8.
35. Y. Zhu, L. Yang, C. Zhang, Y. Tian, F. Zhang and X. Li, Int. J. Biol. Macromol., 2018, 120, 693–701.
36. N. Xie, C. Wu, Q. Ge, J. Zhou, F. Long, Q. Mao, S. Li and H. Shen, Food Funct., 2022, 14, 796–809.
37. J. Yan, W. Wang, L. Li and J. Wu, Carbohydr. Polym., 2011, 85, 753–758.
38. H. Chen, Y. Wu, B. Wang, M. Kui, J. Xu, H. Ma, J. Li, J. Zeng, W. Gao and K. Chen, Int. J. Biol. Macromol., 2024, 262, 130016.
39. M. Snyman, R. E. Walsdorf, S. N. Wix and J. G. Gill, Pigm. Cell Melanoma Res., 2024, 37, 438–452.
40. P. P. Centeno, V. Pavet and R. Marais, Nat. Rev. Cancer, 2023, 23, 372–390.
41. P. Dynoodt, P. Mestdagh, G. Van Peer, J. Vandesompele, K. Goossens, L. J. Peelman, B. Geusens, R. M. Speeckaert, J. L. W. Lambert and M. J. L. Van Gele, J. Invest. Dermatol., 2012, 133, 201–209.
42. H. Y. Park, M. Kosmadaki, M. Yaar and B. A. Gilchrest, Cell. Mol. Life Sci., 2009, 66, 1493–1506.
43. Y. Hu, J. Huang, Y. Li, L. Jiang, Y. Ouyang, Y. Li, L. Yang, X. Zhao, L. Huang, H. Xiang, J. Chen and Q. Zeng, J. Cell. Mol. Med., 2020, 24, 4023–4035.
44. M. Kamilijiang, D. Zang, N. Abudukelimu, N. Aidarhan, G. Liu and H. A. Aisa, Nutrients, 2022, 14, 5044.
45. S. Hu, J. Huang, S. Pei, Y. Ouyang, Y. Ding, L. Jiang, J. Lu, L. Kang, L. Huang, H. Xiang, R. Xiao, Q. Zeng and J. Chen, J. Cell. Physiol., 2018, 234, 7330–7340.
46. M. Pawlikowska, J. Piotrowski, T. Jędrzejewski, W. Kozak, A. T. Slominski and A. A. Brożyna, Phytother. Res., 2019, 34, 173–183.
47. X. Li, Q. Su and Y. Pan, Int. J. Oncol., 2022, 62, 1–11.
48. W. Zhang, J. Yang, J. Chen, Y. Hou and X. Han, Biotechnol. Appl. Biochem., 2005, 42, 9–15.
49. J. Qi, X. Qi, H. Chen and W. Rui, Anti-Cancer Agents Med. Chem., 2023, 24, 132–145.
50. T. Cheng, Y. Li, L. Huang, Z. Li and G. Chen, Trad. Chin. Drug Res. Clin. Pharmacol., 2023, 34, 35–41.
51. C. Hung, B. Hsu, S. Chang and B. Chen, Nutrition, 2011, 28, 98–105.
52. P. Li, D. Nijhawan, I. Budihardjo, S. M. Srinivasula, M. Ahmad, E. S. Alnemri and X. Wang, Cell, 1997, 91, 479–489.
53. Q. Wu, Y. Zhang, Y. Li, G. Alitongbieke, Y. Xue, X. Li, Z. Lin, J. Huang, T. Pan, X. Pan, J. You, J. Lin and Y. Pan, Arch. Biochem. Biophys., 2023, 744, 109678.
54. X. Lai, Y. Chen, R. Huang, F. Zhu, L. Huang, N. Chen, G. Li, W. Hou, Y. Pan and G. Alitongbieke, J. Cancer, 2025, 16, 543–557.
55. S. Wei and W. Chen, Chin. Pharm., 2016, 27, 4363–4366.
56. L. Sun, Z. Lin, X. Duan, J. Lu, Z. Ge, X. Li, M. Li, E. Xing, J. Jia, T. Lan and W. Li, J. Pharm. Pharmacol., 2011, 63, 725–735.
57. L. Xiaoming, L. Kun, Z. Wei, O. Qiuhong, G. Jimin and Z. Jianjun, ACS Appl. Nano Mater., 2024, 7, 28338–28347.
58. J. Lu, L. Sun, Z. Lin, X. Duan, Z. Ge, E. Xing, T. Lan, N. Yang, X. Li, M. Li and W. Li, Phytother. Res., 2013, 28, 200–206.
59. L. Sun, Z. Lin, X. Duan, H. Qi, N. Yang, M. Li, E. Xing, Y. Sun, M. Yu, W. Li and J. Lu, J. Interferon Cytokine Res., 2014, 34, 1–9.
60. Y. Zhang, J. Ma and X. Cheng, Immunol. J., 2021, 37, 380–389.
61. Y. Huang, J. Sheu, T. Jayakumar, C. Chiu, S. Wang and D. Chou, J. Cancer Res. Ther., 2014, 10, 43–49.
62. S. Da Silva Milhorini, D. de Lima Bellan, M. Zavadinack, F. F. Simas, F. R. Smiderle, A. P. de Santana-Filho, G. L. Sassaki and M. Iacomini, Carbohydr. Polym., 2022, 294, 119823.
63. R. S. Oliveira, S. M. P. Biscaia, D. L. Bellan, S. R. F. Viana, M. C. Di-Medeiros Leal, A. F. D. Vasconcelos, L. M. Lião, E. S. Trindade and E. R. Carbonero, Carbohydr. Polym., 2019, 225, 115203.
64. H. Lo, T. Lin, C. Lin, W. Wang, Y. Chen, P. Tsai, J. Su, M. Lu, W. Hsu and T. Lin, Carbohydr. Polym., 2024, 341, 122298.
65. Y. Y. Lee, S. Kim, S. Youn, S. H. Hyun, J. Kyung, G. In, C. Park, H. R. Jung, S. J. Moon, M. J. Kang, E. C. Yi and C. Han, Molecules, 2020, 25, 3019.
66. S. Han, C. W. Lee, J. S. Kang, Y. D. Yoon, K. H. Lee, K. Lee, S. Park and H. M. Kim, Int. Immunopharmacol., 2006, 6, 697–702.
67. H. Tong, G. Jiang, D. Qi, J. Bi, D. Tian, X. Guan, S. Zheng and X. Sun, Carbohydr. Polym., 2016, 156, 244–252.
68. Y. Liu, X. Zou, G. Sun and Y. Bao, Int. J. Biol. Macromol., 2017, 103, 435–440.
69. M. Emanuelli, D. Sartini, E. Molinelli, R. Campagna, V. Pozzi, E. Salvolini, O. Simonetti, A. Campanati and A. Offidani, Antioxidants, 2022, 11, 612.
70. R. Huang, Y. Wang, H. Teng, M. Xu, K. He, Y. Shen, G. Guo, X. Feng, T. Li, B. Zhou, M. Bajenoff, T. Lawrence, Y. Liang, L. Lu and L. Zhang, BMC Biol., 2025, 23, 135.
71. G. Ding, Q. Gong, J. Ma, X. Liu, Y. Wang and X. Cheng, Cancer Sci., 2021, 112, 4050–4063.
72. D. H. Kaplan, V. Shankaran, A. S. Dighe, E. Stockert, M. Aguet, L. J. Old and R. D. Schreiber, Proc. Natl. Acad. Sci. U. S. A., 1998, 95, 7556–7561.
73. L. Xu, M. Kwak, W. Zhang, L. Zeng, P. C. Lee and J. Jin, Oncoimmunology, 2017, 6, e1325981.
74. S. H. Kim, S. W. Lee, H. J. Park, S. H. Lee, W. K. Im, Y. D. Kim, K. H. Kim, S. J. Park, S. Hong and S. H. Jeon, BMC Complementary Altern. Med., 2018, 18, 218.
75. S. Zheng, Y. Jia, J. Zhao, Q. Wei and Y. Liu, Oncol. Lett., 2011, 3, 613–616.
76. A. C. Richard, G. L. Frazer, C. Y. Ma and G. M. Griffiths, Trends Immunol., 2021, 42, 994–1008.
77. L. Xie, G. Liu, Z. Huang, Z. Zhu, K. Yang, Y. Liang, Y. Xu, L. Zhang and Z. Du, Molecules, 2023, 28, 4018.
78. W. Ni, X. Zhang, H. Bi, J. Iteku, L. Ji, C. Sun, J. Fang, G. Tai, Y. Zhou and J. Zhao, Carbohydr. Res., 2009, 344, 2512–2518.
79. L. Sun, Z. Lin, X. Li, M. Li, J. Lu, X. Duan, Z. Ge, Y. Song, E. Xing and W. Li, Basic Clin. Pharmacol. Toxicol., 2010, 108, 149–154.
80. X. Sha, X. Xu, S. Liao, H. Chen and W. Rui, Exp. Cell Res., 2021, 410, 112948.
81. X. Li, Q. Su and Y. Pan, Adv. Clin. Exp. Med., 2024, 33, 533–542.
82. S. Han, C. W. Lee, M. R. Kang, Y. D. Yoon, J. S. Kang, K. H. Lee, W. K. Yoon, K. Lee, S. Park and H. M. Kim, Cancer Lett., 2006, 243, 264–273.
83. M. Yang, Y. Wang and X. Cheng, Chin. Arch. Trad. Chin. Med., 2021, 39, 96–101.
84. Q. Gong, H. Yu, G. Ding, J. Ma, Y. Wang and X. Cheng, Eur. J. Pharmacol., 2021, 916, 174726.
85. W. Wei, J. Wang, K. Aravindaram, S. Wang, C. Hsu, C. Li, C. Wen, J. Sheu and N. Yang, J. Tradit. Complementary Med., 2014, 4, 42–48.
86. M. Kwak, K. Yu, P. C. Lee and J. Jin, Int. J. Biol. Macromol., 2018, 120, 1618–1623.
87. O. A. Bamodu, K. Kuo, C. Wang, W. Huang, A. T. H. Wu, J. Tsai, K. Lee, C. Yeh and L. Wang, Nutrients, 2019, 11, 2264.
88. Y. Wang, H. Wang, K. Chai, S. Guo, Y. Zhai, R. Shi, F. Zhang, J. Huang, Z. Jin, Y. Gao, X. Tao, S. Yang, J. Li, J. Zhou, C. Qiao, A. Stalin and J. Wu, Phytomedicine, 2024, 123, 155242.
89. B. Yang and L. Zhu, Mycosystema, 2024, 43, 129–139.
90. H. Choi, K. Kim, E. Sohn, J. Park, B. Kim, E. Moon, D. Rhee and S. Pyo, Biosci., Biotechnol., Biochem., 2008, 72, 1817–1825.
91. L. Sun, H. Liu, Y. Ye, Y. Lei, R. Islam, S. Tan, R. Tong, Y. Miao and L. Cai, Signal Transduction Targeted Ther., 2023, 8, 418.
92. Y. Liu, B. Sun, G. Zhu, W. Li, Y. Tian, L. Wang, S. Zong, P. Sheng, M. Li, S. Chen, Y. Qin, H. Liu, H. Zhou, T. Sun and C. Yang, Toxicol. Appl. Pharmacol., 2018, 360, 1–8.
93. M. Ma, X. Liu, C. Ma, R. Guo, X. Zhang, Z. Zhang and X. Ren, Int. J. Biol. Macromol., 2023, 226, 1309–1318.
94. H. H. Chandpa, A. K. Panda, C. L. Meena and J. Meena, Vaccine, 2023, 41, 7515–7524.
95. X. Liu, Y. Wang, H. Wu, D. Wang, H. Yao, Z. Ren, Y. Cao, H. Cong and B. Yu, Int. J. Biol. Macromol., 2025, 291, 139137.
96. R. Kang, M. Song, Z. Fang and K. Liu, J. Drug Targeting, 2023, 31, 166–178.
97. Q. Zhang, X. Liu and J. He, J. Mater. Chem. B, 2024, 12, 3336–3355.
98. T. Wang, H. Liu, M. Li, Z. Ji, X. Zhang, N. Wang, Y. Chen, J. Sun and F. Liu, J. Controlled Release, 2025, 380, 539–562.
99. Y. Hu, Y. Wang, Y. Cai, X. Xu, L. Zhao and J. Zhang, Appl. Mater. Today, 2025, 44, 102708.
100. S. M. Tsao, T. C. Wu, J. Chen, F. Chang and T. Tsao, Integr. Cancer Ther., 2021, 20, 1873213688.
101. G. Zhou, H. Liu, Y. Yuan, Q. Wang, L. Wang and J. Wu, Eur. J. Med. Res., 2024, 29, 8.
102. R. Chen, Y. Song, Z. Wang, H. Ji, Z. Du, Q. Ma, Y. Yang, X. Liu, N. Li and Y. Sun, Int. J. Biol. Macromol., 2023, 251, 126288.
103. A. Casillo, A. Fabozzi, I. Russo Krauss, E. Parrilli, C. I. Biggs, M. I. Gibson, R. Lanzetta, M. Appavou, A. Radulescu, M. L. Tutino, L. Paduano and M. M. Corsaro, Biomacromolecules, 2021, 22, 1445–1457.
104. X. Wu, M. Delbianco, K. Anggara, T. Michnowicz, A. Pardo-Vargas, P. Bharate, S. Sen, M. Pristl, S. Rauschenbach, U. Schlickum, S. Abb, P. H. Seeberger and K. Kern, Nature, 2020, 582, 375–378.
105. X. Zhang, L. Hong, B. Zhu, Y. Yuan, S. Li and J. Zhao, Int. J. Biol. Macromol., 2023, 253, 126901.
106. A. Ankur, J. R. Yarava, I. Gautam, F. J. Scott, F. Mentink Vigier, C. Chrissian, L. Xie, D. Roy, R. E. Stark, T. L. Doering, P. Wang and T. Wang, Angew. Chem., Int. Ed., 2025, e202510409.
107. Z. Cui, C. Shi, R. An, Y. Tang, Y. Li, X. Cao, X. Jiang, C. Liu, M. Xiao and L. Xu, ACS Nano, 2025, 19, 2099–2116.
108. J. Liang, Y. Huang, X. Zhu, F. Zhou, T. Wu, J. Jia, X. Liu, H. Kuang and Y. Xia, Carbohydr. Polym., 2024, 346, 122644.
109. C. J. Crawford, G. Reintjes, V. Solanki, M. G. Ricardo, J. Harder, R. Amann, J. Hehemann and P. H. Seeberger, J. Am. Chem. Soc., 2025, 147, 25799–25805.
110. T. Wang, B. Zhu, J. Zhao and S. Li, Chin. J. Nat. Med., 2025, 23, 143–157.
111. C. Yang, C. Lai, Y. Ru, B. Shen, X. Wu, J. Cui, F. Li, C. Zhang, Z. Shi, Q. Qian, C. Xiao, Y. Wang, B. Zhang and Y. Gao, Acupunct. Herb. Med., 2024, 4, 257–270.
112. J. Zhao, X. Feng, J. Han, D. Liu, X. Yang and D. Lin, Int. J. Biol. Macromol., 2025, 320, 145571.
113. J. Guo, S. Zhang, T. Kha, C. Hu and R. Zhu, Angew. Chem., Int. Ed., 2025, e202507581.

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