Recent theranostic applications of hydrogen peroxide-responsive nanomaterials for multiple diseases

Abstract

It is well established that hydrogen peroxide (H₂O₂) is associated with the initiation and progression of many diseases. With the rapid development of nanotechnology, the diagnosis and treatment of those diseases could be realized through a variety of H₂O₂-responsive nanomaterials. In order to broaden the application prospects of H₂O₂-responsive nanomaterials and promote their development, understanding and summarizing the design and application fields of such materials has attracted much attention. This review provides a comprehensive summary of the types of H₂O₂-responsive nanomaterials including organic, inorganic and organic-inorganic hybrids in recent years, and focused on their specific design and applications. Based on the type of disease, such as tumors, bacteria, dental diseases, inflammation, cardiovascular diseases, bone injury and so on, key examples for above disease imaging diagnosis and therapy strategies are introduced. In addition, current challenges and the outlook of H₂O₂-responsive nanomaterials are also discussed. This review aims to stimulate the potential of H₂O₂-responsive nanomaterials and provide new application ideas for various functional nanomaterials related to H₂O₂.

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1 Introduction

As a biomolecule, hydrogen peroxide (H₂O₂) is commonly generated from specifically triggered enzymatic systems and cellular metabolism, and has been linked to the development and progression of multiple diseases.^1–6 Overexpression of H₂O₂ is a typical feature of the microenvironment in numerous diseases.^7,8 It can be catalyzed to produce significant substances, including oxygen (O₂) and hydroxyl radicals (˙OH). The O₂ not only alleviates the hypoxic environment of some diseases such as tumors and inflammation, but also can be converted into singlet oxygen to kill bad cells.^9–11 The ˙OH as a type of reactive oxygen species (ROS) can cause the oxidative stress of cells, which could be beneficial in treating tumors and bacterial infections.¹⁰ However, the ability of H₂O₂ also is a double-edged sword and poses a risk in certain conditions.^12,13 Excessive H₂O₂ induced DNA damage and protein denaturation, resulting in mutations and genetic instability.¹¹ It is unfavorable to the treatment of diseases, such as inflammation, bone injury, cardiovascular diseases, and so on. By observing the changes of H₂O₂ concentration in the lesion, the corresponding physiological and pathological state of the lesion could be detected.¹⁴ Therefore, there should be different choices for catalyzing or consuming H₂O₂ based on different disease types.

With the development of nanotechnology, a growing number of H₂O₂-responsive nanomaterials have been designed and investigated for biomedical applications. H₂O₂-responsive nanomaterials can be simply classified as organic, inorganic, and hybrid nanomaterials. In particular, the core components of H₂O₂-responsive organic nanomaterials mainly are organic molecules and enzymes.^15–18 For example, some organic molecules react with H₂O₂ causing the changes of their absorption or emission characteristics, such as 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS).^3,19 Some enzymes like catalase (CAT) were applied for decomposing H₂O₂, producing O₂ and water.^{16–18,20,21} Compared to organic nanomaterials, inorganic H₂O₂-responsive nanomaterials have greater stability, more functionalities, and a broader range of applications. There inorganic nanomaterials with enzyme-like properties, such as metal oxides and noble metal nanoparticles, were utilized to react with H₂O₂.^22,23 According to the composition of inorganic nanomaterials, the reaction products can be broadly classified as metal ions, O₂ or ROS, etc. And some hybrid nanomaterials formed by the combination of organic and inorganic materials combine their respective advantages and play an important role in H₂O₂-related applications.^24,25

For therapeutic applications, H₂O₂-responsive nanomaterials provided a variety of treatment methods, mainly including producing ROS and consuming H₂O₂.^10,26–30 These nanomaterials employ their characteristics to participate in the treatment of many diseases, including tumors, bacteria, inflammation, cardiovascular diseases, bones, neurologic diseases and ophthalmic diseases.^26,27,31,32 For tumors and bacterial infections, decomposing or catalyzing H₂O₂ often generates other ROS to enhance the treatment effect, while for other diseases such as inflammation, it's crucial to eliminate the oxidative stress of H₂O₂ to foster injury repair and maintain normal physiological state.^{10,26–30,33} The research focused on the elimination of H₂O₂ has also been applied for the treatment of diseases such as inflammation, uveitis, and ischemic stroke.^34–36 Furthermore, H₂O₂-related diagnosis based on H₂O₂-responsive nanomaterials holds promise for the diagnosis of multiple diseases via medical imaging technology like fluorescent imaging (FLI), photoacoustic imaging (PAI), ultrasound (US) imaging, and magnetic resonance imaging (MRI).^37–40 For example, the catalytic decomposition of H₂O₂ produces O₂ bubbles that reflect ultrasound signals in US imaging.⁴¹ Another example, the conversion of ABTS into oxidized ABTS in the presence of H₂O₂ leads to strong near-infrared (NIR) absorbance, thus used for PA imaging.⁴² The combination of H₂O₂-responsive nanomaterials and imaging technology provides a new avenue for disease diagnosis. As more diseases are found to be closely related to H₂O₂, understanding the working principle of H₂O₂-responsive nanomaterials and developing novel and efficient theranostic reagents will unlock additional application channels of H₂O₂-responsive nanomaterials and help address various diseases.

This review summarizes recent advancements in the treatment and imaging of partial diseases associated with H₂O₂, including the design of H₂O₂-responsive nanomaterials and application strategies for different diseases (Fig. 1). The mechanisms and functions of various types of H₂O₂-responsive nanomaterials in the treatment of different diseases are also discussed and summarized. Furthermore, therapeutic applications utilizing H₂O₂-responsive nanomaterials are categorized into two different groups: (1) producing ROS and (2) consuming H₂O₂. The former included tumors, bacterium, dental diseases. The latter included inflammations, cardiovascular diseases, bones, neurologic diseases and ophthalmic diseases. The diagnosis agents that are based on H₂O₂-responsive nanomaterials are utilized for diagnosis purposes in four categories: fluorescence imaging, photoacoustic imaging, ultrasonic imaging, and magnetic resonance imaging. The purpose of this review is to integrate recent findings on H₂O₂-related diseases and H₂O₂-responsive nanomaterials, and to advance the field of H₂O₂-related biomedicine. These strategies and studies allow for better understanding of the functions and mechanisms of H₂O₂-responsive nanomaterials and also open up more possibilities for other biomedical application scenarios.

Fig. 1 Theranostic applications of H₂O₂-responsive nanomaterials, including tumors, bacterium, dental diseases, inflammations, cardiovascular diseases, bones, neurologic diseases, and ophthalmic diseases.

2 H₂O₂-responsive nanomaterials

In this section, the H₂O₂-responsive nanomaterials are introduced that came in three forms (Table 1): organic nanomaterials, inorganic nanomaterials, and hybrid nanomaterials.

Table 1 Categorization of H₂O₂-responsive nanomaterials in recent years

Category		Material	Mechanism	Mode	Ref.
Organic nanomaterials	Small molecules	BSA-MBPB	Boron-carbon link	Releasing drug	Zeng et al.^47
		BODIPY-based photosensitizer	Arylboronate group	Recovering fluorescence	Wang et al.^48
		PF1	Boric acid	Detecting H2O2	Chang et al.^49
		Diselenide based cross-linker nanomaterial	Diselenide bridges	Releasing DOX	Jo et al.^51
		HKPerox-1 and HKPerox-2	Payne/Dakin reaction	Molecular recognition of H2O2	Ye et al.^54
		DPPEA-HC	Reaction of triphenylphosphine	Detecting H2O2	Soh et al.^56
		ABTS	Oxidation reaction	Photoacoustic imaging	Ding et al.^57
	Enzymes	HA-CAT@aCe6	Catalase	Producing O2	Phua et al.^63
		PLGA-R837@Cat	Catalase	Relieving the tumor hypoxia	Chen et al.^64
	Organic polymer nanoparticles	PVAX polymer nanoparticles	Peroxalate ester linkages	Decreasing H2O2 and releasing drug	Park et al.^66
		POD-PEG NPs	Oxalate ester bond	Releasing drug	Ou et al.^67
		Block copolymer NPs	Change of particle size	Releasing drug	Phan et al.^65
		SCNPs	Heavy-atom effect	Detecting H2O2	Lu et al.^68
		Metalloporphyrin-based porous organic polymer	POD-like activity	Detecting H2O2	Liu et al.^69
	Hydrogels	Hydrogel based on the thiazolidinone group	Gel–sol phase transition	Releasing drug	Ren et al.^71
		L012@PAni-PAAm hydrogels	Biosensors	Monitoring H2O2	Guo et al.^72
Inorganic nanomaterials	Metal oxides	MnO2@PtCo nanoflowers	Catalase mimic	Relieving hypoxic condition	Wang et al.^81
		IR780-sMnO2-PCM NPs	Catalase mimic	Producing O2	Zhang et al.^82
		Co3O4 NPs	Oxidase mimic and peroxidase mimic	Detecting H2O2	Zhang et al.^85
	Metal ions	H–MnO2@TPyP@Bro	Generating ˙OH by Mn^2+	Chemodynamic therapy	Zhu et al.^90
		Fe(III)@WS2-PVP NPs	Fenton reation	Chemodynamic therapy	Wu et al.^91
	Single-atom enzyme	Fe-SANzyme nanozymes	Catalase-like activity	Producing O2	Zhang et al.^96
		Pd-based SAzyme	POD mimic	Generation of ˙OH	Zhu et al.^97
	Noble metal nanoparticles	SiO2–Pt	CAT mimic	Producing O2	Lyn et al.^104
		Ru nanoframes	POD mimic	Generation of ˙OH	Ye et al.^107
Hybrid nanomaterials	Metal–organic frameworks	ICG@Mn/Cu/Zn-MOF@MnO2	Producing ˙OH by Cu^+ and Mn^2+	CDT	Cheng et al.^24
		GOx@ZIF@MPN	Producing ˙OH by Fe^2+	CDT	Zhang et al.^113
	Quantum dots and their capping agents or coating	MPA capped CdTe QDs	Fluorescence signal change	Detecting H2O2	Castro et al.^115
		Si–CdTe hybrid QDs	Cd–S bond	Detecting H2O2	Zhou et al.^116
		Cy5-labeled HRP–QDs	Fluorescence change	Detecting H2O2	Huang et al.^118
	Noble-metal nanoclusters and organic protective agents	AgNCs protecting BSA	Dual-emission fluorescent	Detecting H2O2	Chen et al.^120
		AgNCs protecting [C4py]^124	Coordination bond between AsO3^3− and π molecular orbitals	Detecting H2O2	Wang et al.^121

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2.1 H₂O₂-responsive organic nanomaterials

Organic nanomaterials possess unique advantages, such as biosafety and easy synthesis. We summarize some H₂O₂-responsive organic nanomaterials, including small molecules, enzymes, organic polymer nanoparticles and hydrogels.

2.1.1 Small molecules.
2.1.1.1 Boronate-based small molecules. Recently, boronate-based molecules have been reported as H₂O₂-responsive organic molecules, which can be selectively hydrolyzed by H₂O₂.¹⁵ Its reaction with H₂O₂ was mainly based on the cleavage of the formed boron-carbon link.⁴³ Boronate-based organic nanoparticles were widely used in the biomedical field, including H₂O₂-responsive drug delivery and detection.^44–46

For example, Zeng et al. designed a pro-photosensitizer MBPB based on boron-carbon link, which could be hydrolyzed by H₂O₂ and achieved responsive release of methylene blue (MB) and quinone methide (QM) in Fig. 2a.⁴⁷ After being ingested by tumor cells, the MBPB under the activation of H₂O₂ would release MB to produce ¹O₂ and QM to enhance oxidative stress, and finally play a role in enhancing photodynamic therapy. Moreover, Wang et al. designed a H₂O₂-responsive photosensitizer contained a diiodo distyryl boron dipyrromethene (BODIPY) core and an arylboronate group, which quenched the fluorescence signal of BODIPY by photoinduced electron transfer (PET).⁴⁸ The arylboronate group did not break without H₂O₂, and the fluorescence of PET was still inhibited. However, in the presence of H₂O₂, the strong fluorescence emission would be produced by BODIPY. Herein, the combination of arylboronate group and BODIPY as H₂O₂-responsive fluorescence nanomaterials had enormous potential. Chang and coworkers reported a peroxyfluor-1 (PF1) molecule which could be used for detecting H₂O₂ in living cells via fluorescence signals change (Fig. 2b).⁴⁹ PF1 used the boric acid deprotection mechanism to detect H₂O₂ in aqueous solutions of reactive oxygen species, providing an unprecedented selectivity and optical dynamic range.

Fig. 2 (a) A schematic diagram illustrating of MBPB to deliver methylene blue. Reproduced from ref. 47 copyright 2019, Elsevier Ltd. (b) A schematic diagram illustrating H₂O₂-related fluorescent conversion of PF1. Reproduced from ref. 49 copyright 2004, American Chemical Society. (c) Schematic of a tandem Payne/Dakin reaction. Reproduced from ref. 54 copyright 2018, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (d) A schematic diagram illustrating the fluorescence intensity of DPPEA-HC enhanced. Reproduced from ref. 56 copyright 2004, Elsevier Ltd. (e) A schematic diagram illustrating the conversion of ABTS in the presence of H₂O₂. Reproduced from ref. 57 copyright 2019, American Chemical Society. (f) The preparation process of HA-CAT@Ce6 by the conjugation of HA with CAT. Reproduced from ref. 63 copyright 2019, American Chemical Society. (g) Schematic of PLGA to encapsulate CAT. Reproduced from ref. 64 copyright 2019, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (h) Schematic of the evolution of particle size and morphology of H₂O₂-sensitive block copolymer NPs. Reproduced from ref. 65 copyright 2022, American Chemical Society. (i) Schematic of releasing drugs via H₂O₂-responsive hydrogels. Reproduced under terms of the CC-BY license.⁷¹ Copyright 2017, Chunhua Ren, published by RSC Advances.

2.1.1.2 H₂O₂-responsive diselenide bridges. Similar to the B–C link, the diselenide bridge could be also cleaved by H₂O₂.⁵⁰ Based on this, H₂O₂-responsive diselenide bridges were often used for controllable drug delivery. For example, Jo et al. designed H₂O₂-stimuli responsive nanomaterials based on diselenide bridges, which showed a rapid release of doxorubicin (DOX) in the presence of H₂O₂.⁵¹ The diselenide bridge could be cleaved and converted to seleninic acid, providing a good direction for biomedical research.⁵² Not only that, some selenide-based nanoparticles can produce fluorescence via the oxidation of H₂O₂.⁵³
2.1.1.3 Other small molecules. In addition, some molecules can also serve as probes to achieve H₂O₂ detection by reacting with H₂O₂.¹⁵ For example, Ye et al. reported novel fluorescent probes HKPerox-1 and HKPerox-2 based on the H₂O₂-responsive group and tandem Payne/Dakin reaction to molecular recognition of H₂O₂ (Fig. 2c).⁵⁴ A benzopyrylium-coumarin (BC) probe has been reported to detect H₂O₂.⁵⁵ And a fluorescent probe 7-hydroxy-2-oxo-N-(2-(diphenylphosphino)ethyl)-2H-chromene-3-carboxamide (DPPEA-HC) consisting of a 7-hydroxycoumarin moiety and a diphenylphosphine moiety have been designed to detect H₂O₂ (Fig. 2d).⁵⁶ Not only that, ABTS could be converted into oxidized ABTS in the presence of H₂O₂.⁵⁷ As depicted in Fig. 2e, oxidized ABTS possessed strong NIR absorbance, which could be used for PA imaging. Therefore, this implies that organic molecules-based nanomaterial may be an effective nanoplatform for H₂O₂-related diseases treatment and diagnosis.

2.1.2 Enzymes. There are amounts of enzymes that can react with H₂O₂, such as CAT, superoxide dismutase (SOD), horseradish peroxidase (HRP), peroxidase (POD) and so on.^58–60 For example, CAT, a H₂O₂-metabolizing enzyme, can catalyze H₂O₂ to generate O₂, which is an important pathway for H₂O₂ metabolism.^61,62 Then, the generation of O₂ can be used to alleviate hypoxia tumor microenvironment (TME) or convert to ROS. The involvement of CAT in tumor therapy is a major trend in biomedical fields. However, as a natural enzyme, it is easy to leak into the normal tissue before entering the tumor area, thus affecting the activity of normal cells. Similarly, its activity during the transportation is affected by the surrounding environment. To prevent organic molecules or enzymes' premature leakage and improve their delivery, nanocarriers were usually used to load them into disease regions. Organic carriers loading H₂O₂-related enzymes have the advantages, of high loading efficiency and good biocompatibility.⁶³ For instance, hyaluronic acid (HA) served as a biodegradable carrier to load CAT by covalent conjugation, which had tumor-targeting ability (Fig. 2f).⁶³ The encapsulated CAT could decompose endogenous H₂O₂ to produce oxygen and relieve hypoxia in situ. In other study, Chen et al. synthesized a core–shell nanoparticle-based poly(lactic-co-glycolic) acid (PLGA) to encapsulate CAT in order to protect CAT in Fig. 2g.⁶⁴

2.1.3 Organic polymer nanoparticles. It is becoming increasingly apparent that organic polymer nanoparticles are widely used in H₂O₂-responsive biomedical fields because of their stability advantage.⁶⁵ For example, Park et al. synthesized polyoxalate containing vanillyl alcohol (PVAX) polymer nanoparticles for H₂O₂ scavenging and drug release.⁶⁶ Ou et al. designed prodrug-delivery nanoplatforms based on podophyllotoxin (POD) prodrug linking with poly(ethylene glycol)(n)monomethacrylate.⁶⁷ In the presence of H₂O₂, POD drugs could be released by a self-sacrificing pathway. In another study, Phan et al. reported the evolution of particle size and morphology of H₂O₂-sensitive block copolymer NPs from spherical micelles, fused micelles, to vesicles over time (Fig. 2h).⁶⁵ Not only that, polymers could also be used to detect H₂O₂.⁶⁸ Fluorescent single-chain polymer nanoparticles (SCNPs) with aggregation-induced emission (AIE) were used for H₂O₂ detection through intermolecular heavy-atom effect. Liu and coworkers designed a metalloporphyrin-based porous organic polymer which exhibited excellent peroxidase-like activity for detecting H₂O₂.⁶⁹ The polymer possessed a wide linear range of 50–1800 μM and a relative lower limit of detection (LOD) of 26.70 μM for H₂O₂. Therefore, the polymer could accurately detect the change of H₂O₂ under physiological and pathological conditions.

2.1.4 Hydrogels. As a safe material, hydrogels have many advantages, such as high porosity, which is conducive to substance exchange and drug loading.⁷⁰ At the same time, hydrogels are sensitive to external stimuli, such as pH, redox, and so on.⁷¹ Therefore, these advantages can be utilized to design hydrogels with H₂O₂-response for drug delivery or H₂O₂ detection. For example, Ren et al. designed a novel H₂O₂-responsive hydrogel based on the thiazolidinone group.⁷¹ With the addition of H₂O₂, hydrogels underwent gel–sol phase transition, which was used for drug release (Fig. 2i). In other studies, hydrogels also had great applications in the field of biosensing.^72–74 Guo et al. designed L012@PAni-PAAm hydrogels as biosensors to monitor H₂O₂ produced from cardiomyocytes.⁷²

In conclusion, organic nanomaterials play a very important role in H₂O₂-related biomedical applications. Reasonable design of organic nanomaterials with higher safety, better therapeutic efficiency and more functionality is the focus of future research.

2.2 H₂O₂-responsive inorganic nanomaterials

Owing to the advancement of nanotechnology, many inorganic materials now have possessed enzyme-mimic catalytic effects, mainly including oxidase-like, peroxidase-like, CAT-like, and superoxide dismutase-like.^75,76 Compared with natural enzymes, inorganic materials have amounts of advantages, such as facile fabrication, low cost, and robust stability against severe conditions.⁷⁷ In this part, we list four types of H₂O₂-responsive inorganic nanomaterials: metal oxides, metal ions, single-atom nanozymes, and noble metal nanoparticles.

2.2.1 Metal oxides. Currently, various metal oxide inorganic materials, which served as enzyme mimics have been reported that could directly or indirectly react with H₂O₂, such as manganese (Mn), cobalt (Co), cerium (Ce), and ruthenium (Ru).^78–80 For example, H₂O₂ would be catalyzed to O₂ by manganese dioxide (MnO₂).⁸¹ Then, the increasing concentration of O₂ could be used to enhance the therapeutic effect of various oxygen-dependent therapeutic methods. As shown in Fig. 3a, Zhang et al. loaded MnO₂ and IR780 into a thermal-responsive phase-change material (IR780-sMnO₂-PCM NPs) for enhancing the photodynamic therapy effect.⁸² In addition to Mn, Co-based metal oxides have been proven that possessed SOD-like, CAT-like, and POD-like catalytic activities.^83,84 Based on those, cobaltosic oxide (Co₃O₄) nanoparticles have been designed as biosensing platforms to detect H₂O₂.⁸⁵ In another study, Ce-based metal oxides have been reported that the ratio of Ce³⁺/Ce⁴⁺ determined the enzyme-like properties, such as CAT mimic.⁸⁶ In addition, vanadium (V)-based and titanium (Ti)-based metal oxides exhibited POD-like activity that has been reported.^87,88

Fig. 3 (a) The synthetic process of IR780-sMnO₂-PCM NPs. Reproduced from ref. 82 copyright 2019, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (b) Schematic of Fe(III)@WS₂-PVP nanocapsules to generate Fe²⁺ and trigger a Fenton reaction. Reproduced from ref. 91 copyright 2018, American Chemical Society. (c) Schematic of The Fe-SAzyme exhibited CAT-like capacity to decompose H₂O₂ to O₂. Reproduced from ref. 96 copyright 2022, Wiley-VCH GmbH. (d) Schematic of Pt NPs catalyzed H₂O₂ and the synthetic process of Pt NPs. Reproduced from ref. 104 copyright 2021, American Chemical Society. (e) Schematic of TA reducing Fe(III) to Fe(II). Reproduced from ref. 113 copyright 2018, American Chemical Society. (f) The schematic of MPA-CdTe QDs to detect H₂O₂. Reproduced from ref. 115 copyright 2019, Elsevier B.V. (g) Schematic of Si–CdTe hybrid QDs to detect H₂O₂. Reproduced from ref. 116 copyright 2022, Wiley-VCH GmbH. (h) Schematic of QDs labeled Cy5 to detect H₂O₂. Reproduced from ref. 118 copyright 2012, Elsevier B.V.

2.2.2 Metal ions. As with metal oxides, metal ions can also react with H₂O₂, such as Mn ions (Mn²⁺), Fe ions (Fe²⁺), cuprum ions (Cu²⁺), and so on.⁸⁹ The main mechanism of the reaction with H₂O₂ is Fenton or Fenton-like reaction. For example, Zhu et al. synthesized a nanoplatform that could release Mn²⁺ in the presence of overexpressed glutathione (GSH).⁹⁰ Subsequently, Mn²⁺ was oxidized by H₂O₂ and generated toxic ˙OH. Besides Mn ions, Fe(III)@WS₂-PVP nanocapsules to generate Fe²⁺ and trigger a Fenton reaction have been designed (Fig. 3b).⁹¹ In the nanocapsule, the Fe(III) was reduced to form Fe²⁺ by WS₂. Then, the continuously generated Fe²⁺ reacted with H₂O₂ to produce ˙OH in tumor cell. The same as irons, Cu²⁺ and Co²⁺ have been proven to trigger the H₂O₂ to generate ˙OH.^92,93

2.2.3 Single-atom nanozymes. Recently, a single-atom enzyme (SAzyme) has been reported to apply for developing H₂O₂-related biomedicines due to its unique catalytic properties.⁹⁴ For example, SAzyme possesses POD-like activity which catalyzed H₂O₂ into ˙OH in the TME.^95,96 Zhang et al. designed an Fe-based SAzyme by edge-site engineering, which exhibited CAT-like capacity to decompose H₂O₂ to O₂, and the edge-site engineering would enhance the CAT-like activity (Fig. 3c).⁹⁶ The Fe-SANzyme significantly removed ROS and reduced oxidative stress through CAT-like catalysis, thereby eliminating pathological angiogenesis in animal models of retinal angiopathies without affecting normal vascular repair. And a novel palladium (Pd)-based SAzyme, which could generate ˙OH in the presence of H₂O₂ has been synthesized.⁹⁷ At present, the research on H₂O₂-related SAzymes is still in its infancy, and it will be a hot spot in future research.

2.2.4 Noble metal nanoparticles. Like metal oxides, some noble metal nanoparticles can produce or consume H₂O₂, such as aurum (Au), platinum (Pt), ruthenium, and palladium.^{83,94,98–100} For example, Pt, a common noble metal, is often used to catalyze H₂O₂ due to its CAT-like ability, electrochemical production, etc.^101–103 As depicted in Fig. 3d, silicon dioxide (SiO₂)–Pt NPs have been designed, which could decompose H₂O₂ to O₂ as like CAT.¹⁰⁴ In other research, a motor that combined Au and Pt moved along a stable direction by the catalytic decomposition of H₂O₂.¹⁰⁵ And, Ru nanoparticles and Pd-based nanozymes have been proven that exhibited HRP, CAT, or POD-like activities.^100,106 Ye et al. reported Ru nanoframes with an octahedral shape that were three times more active than natural POD.¹⁰⁷ Furthermore, noble metal alloy nanoparticles, such as iridium (Ir)/Ru and Pt/Cu alloy nanoparticles, also exhibited enzyme-like activities.^108,109 Thus, the applications of noble metal in H₂O₂-responsive nanomaterials are showing great potential for the theranostic of diseases.

2.3 Hybrid nanomaterials

Most hybrid nanomaterials are composed of close integration of organic components, inorganic components, or dual types of ingredients.¹¹⁰ Hybrid materials can combine the advantages of organic and inorganic materials for more efficient biological applications.

2.3.1 Metal–organic frameworks. Metal–organic frameworks (MOFs), a type of hybrid material, are consisted of metal ions (or clusters) and organic groups, and their role in nanomaterials is becoming central.¹¹¹ Recently, many researches have shown that MOF could serve as a nanozyme, which would react with H₂O₂.¹¹² For example, Cheng et al. reported a nanoplatform ICG@Mn/Cu/Zn-MOF@MnO₂ that could be used for synergistic tumor treatment.²⁴ The nanoplatform could release Cu⁺ and Mn²⁺ to catalyze H₂O₂ into ˙OH in tumor cells. More than that, the organic components of MOF could assist inorganic components for H₂O₂-related applications. For instance, tannic acid (TA) could quickly reduce Fe(III) to Fe(II), and then Fe(II) catalyzed H₂O₂ to ˙OH (Fig. 3e).¹¹³

2.3.2 Quantum dots and their capping agents or coating. Because of their unique optical properties, quantum dots (QDs) were widely used for fluorescence-based sensing.¹¹⁴ H₂O₂-sensitive QDs have been designed to detect H₂O₂ via coating organic molecules.¹¹⁴ Castro et al. designed a 3-mercaptopropionic acid (MPA) capped cadmium telluride (CdTe) QDs with orange-emitting and combined with a blue-emitting carbon dot (CD).¹¹⁵ When H₂O₂ was not present, MPA-CdTe QDs and CDs could produce fluorescence signals of different wavelengths, respectively (Fig. 3f). With the addition of H₂O₂, the emitting fluorescence of MPA-CdTe QDs was decreased while the emitting fluorescence of CDs remained constant. The change of fluorescence signal was linearly correlated with H₂O₂. Using this special fluorescence signal change, it could be used as a method to determine H₂O₂. In another study, water-soluble Si–CdTe hybrid QDs have been designed to detect H₂O₂.¹¹⁶ In the presence of H₂O₂, the fluorescence of CdTe QDs was extinguished due to the breakage of the Cd–S bond (Fig. 3g). Furthermore, Te-doped CDs have been reported to scavenge H₂O₂ for protecting normal cells.¹¹⁷ In addition to fluorescence attenuation, QDs-related fluorescence enhancement could also be used to detect H₂O₂. For example, Huang et al. reported a new strategy of fluorescence resonance energy transfer (FRET) for enhanced fluorescence in the HRP-catalyzed oxidation with H₂O₂.¹¹⁸ In the presence of H₂O₂, the QDs served as a fluorescent donor, and the tyramide labeled Cy5 served as an acceptor to generate a fluorescent wavelength of 670 nm (Fig. 3h).

2.3.3 Noble-metal nanoclusters and organic protective agents. Noble-metal nanoclusters can be served as biomedical probes to detect H₂O₂ due to their excellent fluorescence properties.¹¹⁹ Chen et al. utilized bovine serum albumin (BSA) as a stabilizer to synthesize argentum nanoclusters (AgNCs), which could be applied for selectively H₂O₂ detection.¹²⁰ Wang et al. prepared a fluorescent probe AgNC which was collaboratively composed of pyridinium-based ionic liquid.¹²¹ The original fluorescence could be quenched by the coordination bond between AsO₃³⁻ and π molecular orbitals. With the addition of H₂O₂, AsO₃³⁻ could be oxidized to AsO₄³⁻ and the origin fluorescence would recover. In addition to Ag, Au nanoclusters (HRP-AuNCs) have also been used to investigate H₂O₂ secretion at the single-cell level.¹²² Not only that, organic agents-stabilized Cu nanoclusters have also served as H₂O₂-responsive fluorescent probes in biomedical applications.¹²³

To summarize, an increasing number of H₂O₂-responsive nanomaterials, such as organic, inorganic, and hybrid nanomaterials, are being employed in a variety of biological applications. Future research will also concentrate on the discovery novel nanomaterials as well as the advancement of existing nanomaterials. In the subsequent sections, we summarize and review the various biomedical applications of novel nanomaterials, including disease therapy and imaging.

3 The mechanism of H₂O₂-responsive nanomaterials for biomedical applications

The mechanism of H₂O₂ responsive nanomaterials can be broadly divided into three categories: (1) utilize H₂O₂ to change the state of organic molecules; (2) eliminate H₂O₂ and produce oxygen; (3) catalyze H₂O₂ to produce hydroxyl radical. For the former (1), the H₂O₂ can directly affect the nanomaterials composed of ABTS molecules, aromatic boronates-based molecules, or fluorescent molecules, causing the change of their characteristic absorption or emission peak, or the cleavage of molecules. For the latter (2) and (3), the by-products such as O₂, ˙OH, and metal ions, generated by those nanomaterials and H₂O₂ reactions played central role in their biological applications. For example, the generation of ˙OH by catalyzing H₂O₂ can cause oxidative stress, which can then induce tumor cells or bacterial death. The generation of O₂ by decomposed H₂O₂ can alleviate hypoxia, or be converted into ¹O₂, or be used as US contrast agents for enhancing the effect of disease treatment. Another example, a lot of ions can react with H₂O₂ through a Fenton reaction or a Fenton-like reaction and can be monitored by magnetic resonance imaging. Here, we listed the main usage mechanisms of H₂O₂ (Fig. 4).

Fig. 4 The typical mechanism of H₂O₂-responsive nanomaterials in the biomedical applications.

4 Biomedical applications of H₂O₂-responsive nanomaterials

The occurrence and progression of many diseases are closely related to H₂O₂ levels. Reasonable selection of H₂O₂ treatment methods is of great help into the treatment and diagnosis of diseases. H₂O₂-related diseases treatment mainly relies on oxidative stress from H₂O₂ generated ROS, increasing oxygen content for various therapy methods and removing H₂O₂. Thus, the H₂O₂-responsive nanomaterials are categorized into two different groups: (1) producing ROS and (2) reducing oxidative stress. The former included tumors, bacterium, dental diseases. The latter included inflammations, cardiovascular diseases, bones, neurologic diseases and ophthalmic diseases. H₂O₂-related imaging diagnosis are based on the release product of nanomaterials after interacting with H₂O₂, such as gas bubbles, metal ions, and fluorescence signal changes. Herein, we provide an overview of current researches on H₂O₂-related various therapy and imaging detection applications (Table 2).

Table 2 Categorization of H₂O₂-responsive nanomaterials in recent years

Research field	Method	Nanomaterial	Mechanism	Application	Ref.
Tumors	Treatment	Mn-CDs	Produce O2	Enhanced PDT	Jia et al.^7
		Ce6-DNAzyme NPs	Convert H2O2 to ˙OH for type I PDT	Combined type I and II PDT	Liu et al.^27
		CSI@Ex-A	Produce O2 via CAT	Enhanced SDT	Wu et al.^138
		HMONs-MnOx	Produce O2 via Mn-based nanozymes	Enhanced SDT	Zhu et al.^140
		GDY–CeO2–miR181a–PEG–iRGD	Produce O2 via CeO2	Enhanced RT	Zhou et al.^143
		AVPt@HP@M	Produce O2 via Pt NPs	Enhanced RT	Gong et al.^141
		PLGA-R837@CAT	Produce O2 via CAT	Enhanced immunotherapy	Chen et al.^64
		AFe NPs	Generate ˙OH via Fe^2+	Enhanced CDT	Chen et al.^158
	Imaging	MS@MnO2 NPs	Deplete GSH and produce ˙OH	Enhanced CDT	Lin et al.^159
		Cu2MoS4@GOx	Enhance multiple enzyme effect	Synergistic therapy	Chang et al.^21
		ACD	Turn on the fluorescence	H2O2-responsive FLI	Zhao et al.^171
		Ag/Ag2S NPs	Turn on the fluorescence	FLI of liver injury and tumor	Zhang et al.^172
		GQDzyme/ABTS NPs	Convert ABTS into oxidized ABTS	PAI of nasopharyngeal carcinoma in vivo	Ding et al.^57
		LOD/CAT-loaded nanogels	Generate abundant O2 gas	Efficient diagnostic nanoprobes of US imaging	Wu et al.^180
		AuNCs@mSiO2@MnO2	Release Mn^2+	Enhanced MRI signal intensity	Yin et al.^185
		MnPcE4	Achieve trimodal imaging	Achieved multimodal imaging	Wang et al.^187
Bacterium	Treatment and imaging	CoIITBPP(bpy) nanozymes	Enhance CAT-like activity	Enhanced PDT	Hu et al.^8
		Pd@Pt-T790 NPs	Produce O2 via Pt NPs	Enhanced PDT and combined PAI and MRI	Sun et al.^191
		Cu2O NPs	Catalyze H2O2 to ˙OH	Combined CDT and PAI	Yang et al.^193
		Ce6@Arg-ADP NPs	Produce NO via H2O2	NO therapy	Zhu et al.^33
Dental diseases	Treatment and imaging	TiO2/Pt tubular robots	Generate bubbles and ˙OH	Oral biofilm disruption	Villa et al.^196
		Dex-IONP-GOx NPs	Generate ˙OH	Prevent dental caries	Huang et al.^13
		CuO/BP nanosheets	Conversion from H2O2 to O2 is related valence change of Cu	Assessment of disease progression and treatment effectiveness	Wang et al.^197
Inflammations	Treatment	2D-TMD nanosheets	Scavenge intracellular H2O2	Anti-inflammation	Yim et al.^32
		Hollow microspheres	Release drugs and CO2 gas by H2O2	Anti-inflammation	Chung et al.^200
	Imaging	TMSN@PM	Reaction with H2O2 and degrades itself to release Mn^2+	Switch of MRI signal	Li et al.^203
		Au–Pd@Ag nanorods	Variate absorption via H2O2	Therapeutic effect evaluation by PAI	Ye et al.^34
		CUR-PVAX NPs	Degrade peroxalate ester to generate CO2 bubbles	Potential US agents of ischemic diseases	Jung et al.^204
		Co complexes	Utilizing the large change in chemical shift shown at 19F	Therapeutic effect evaluation by MRI	Yu et al.^205
Cardiovascular diseases	Treatment	Hydrogels contained CAT	Scavenge H2O2	MI repair	Ding et al.^209
		nCe-decorated nanofibers	Scavenge H2O2	Cardiac hypertrophy inhibition	Jain et al.^210
		Fu-sBR nanoassemblies	Scavenge H2O2	Thrombosis treatment	Jung et al.^211
	Imaging	BSA-Cy-Mito nanoprobes	Produce PAI signal	Atherosclerotic plaque vulnerability assessment and precise treatment	Gao et al.^212
Bone injury	Treatment and imaging	Pt/CeO2 nanozymes	Multiple enzyme effects scavenge uric acid and H2O2	Treatment of MSU-induced acute gout	Lin et al.^230
		PUDCA NPs	Scavenge H2O2 and release UDCA	The osteogenic differentiation of MSCs	Arai et al.^5
		Fe3O4@GO/BMP2	Reduce H2O2 and capture ˙OH	Bone tissue regeneration	Zhang et al.^232
		hMNP/GelMA composite hydrogels	Scavenge H2O2 and release Mn^2+ for promoting osteogenesis	Bone tissue regeneration	Li et al.^234
Neurologic diseases	Treatment	Ma@(MnO2 + FTY) NPs	Convert H2O2 to O2	Protect damaged neurons	Li et al.^238
	Imaging	PCAB	Detect H2O2	Therapeutic effect evaluation by FLI	Wang et al.^240
		CRANAD-88	Amplifying NIR fluorescence signals	Monitoring the changes of H2O2 concentrations before and after treatment	Yang et al.^241
Ophthalmic diseases	Treatment	CeNP-CL	Scavenge H2O2	Treatment of ophthalmic diseases	Choi et al.^245

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4.1 Enhanced tumor therapy effect by producing ROS and correlated imaging

As a major threat to human health, it has always been the goal of tumor nanomedicine to develop effective treatments.¹²⁵ In this section, we will provide an overview of current researches on H₂O₂-involving tumor therapy and diagnosis.

4.1.1 Enhanced tumor therapy by enhancing ¹O₂ production and alleviating hypoxia. Photodynamic therapy (PDT), sonodynamic therapy (SDT), radiotherapy (RT), radiodynamic therapy (RDT) and immunotherapy have emerged as novel tumor treatment strategies as a result of the advancement of nanotechnology.^64,126–129 The main mechanism of PDT, SDT, and RDT is the transfer of electrons or energies from sensitizers to adjacent substrates, under light, US, or X-ray irradiation, followed by the production of ROS.⁹ While the main mechanism of enhanced RT and immunotherapy is changing the microenvironment of RT and the immune by alleviating hypoxia. The concentration of O₂ plays a key role in those therapies, which are positively correlated with the therapeutic effect. However, due to the rapid proliferation of tumor cells and insufficient blood supply, hypoxia becomes an important characteristic of tumors.¹³⁰ If the oxygen tension falls below 10 mmHg, tissue is generally classified as hypoxic.¹³¹ Hypoxia-inducing factor 1 (HIF-1) is considered to be the main regulatory factor for cell adaptation to hypoxia, which is closely related to tumor progression and therapeutic effect.¹³² It can make cells and tissues produce a series of reactions to adapt to hypoxia environment, promote tumor angiogenesis, and increase the tumor's own invasiveness and resistance to treatments.^4,26,29,133 Strategies for O₂ generation have been reported include exogenous delivery of O₂ to tumor region, or inhibition of mitochondrial respiration in tumor cells.⁹ However, these methods all encountered the problem of insufficient oxygen loading effect.⁹ At present, the decomposition of overexpressed H₂O₂ into O₂ by nanomaterials become an important method to alleviate hypoxia.⁹
4.1.1.1 Enhanced photodynamic therapy. PDT mainly uses photosensitizer to generate energy level transition under the excitation of light and enter the excited state of higher energy level.¹³⁴ Then, as the photosensitizer returns to its ground state, it needs to release a charge or energy to its surroundings. The substrate molecules around the photosensitizer gain this charge or energy to form ROS. PDT are divided into type I and type II by obtaining differences in charge or energy. PDT could be divided into type II (enhancing treatment by H₂O₂) and type I (direct treatment with H₂O₂) as shown in Fig. 5a.¹³⁵ The mechanism of type II was that converted O₂ from the decomposition of H₂O₂ into ¹O₂. For instance, Jia and coworkers synthesized a nanoplatform (Mn-CDs) to enhance PDT.⁷ Mn-CDs served as a CAT-like nanozyme to produce O₂ by H₂O₂, then as a photosensitizer to convert O₂ to ¹O₂. The amount of ¹O₂ produced was closely correlated with the concentration of O₂. The mechanism of type I was that the excited photosensitizer under light irradiation could react with adjacent substrates by electron transfer to produce ROS.¹³⁶ A GSH-responsive-release nanoplatform for H₂O₂-related type I PDT under 808 nm laser irradiation have been designed (Fig. 5b).²⁷ The nanosheet could not only convert H₂O₂ to ˙OH under 808 nm laser irradiation for type I PDT, but also convert O₂ to ¹O₂ under 660 nm laser irradiation for type II PDT. As shown in Fig. 5c and d, through DCFH-DA fluorescence in cells it was not difficult to find that the nanomaterial could produce ROS through type I and type II PDT under laser irradiation of different wavelengths. Moreover, cell viability in Fig. 5e and live/dead staining imaging in Fig. 5f showed that the killing ability of this nanomaterial against MCF-7 cells.

Fig. 5 (a) Schematic of the difference between type I and type II. Reproduced from ref. 135 copyright 2021, Wiley-VCH GmbH. (b) Schematic of the nanoplatform to convert H₂O₂ to ˙OH for tumor treatment. Reproduced from ref. 27 copyright 2021, Wiley-VCH GmbH. (c) Confocal images of intracellular ROS generation. Reproduced from ref. 27 copyright 2021, Wiley-VCH GmbH. (d) ROS fluorescence signals generated during different treatments. Reproduced from ref. 27 copyright 2021, Wiley-VCH GmbH. (e) Cell viability of MCF-7 cells with different treatments. Reproduced from ref. 27 copyright 2021, Wiley-VCH GmbH. (f) Live/dead staining images of MCF-7 cells with different treatments. Reproduced from ref. 27 copyright 2021, Wiley-VCH GmbH. PBS (i), 660 and 808 nm laser irradiation (ii), Ce6-cDNA/[Cu(tz)] (iii), Ce6-DNAzyme/[Cu(tz)] (iv), Ce6-cDNA/[Cu(tz)] under 660 nm laser irradiation (v), [Cu(tz)] under 808 nm laser irradiation (vi), Ce6-DNAzyme/[Cu(tz)] under 660 nm laser irradiation (vii), and Ce6-DNAzyme/[Cu(tz)] under 660 and 808 nm laser irradiation (viii).

4.1.1.2 Enhanced sonodynamic therapy. SDT was also an excellent method of tumor therapies, which could generate ROS and possess maximum tissue-penetration depth.^28,137 Thus, the increasing concentration of O₂ could also enhance the effect of SDT. Inspired by the fact that H₂O₂ produced oxygen by CAT, Wu et al. designed a nanoplatform CSI@Ex-A for enhancing SDT (Fig. 6a).¹³⁸ The generated O₂ from the decomposition of H₂O₂ by CAT would be converted to ¹O₂ by indocyanine green (ICG) under US irradiation. According to the HIF-1ɑ fluorescence pattern analysis in Fig. 6b, it could be seen that CAT decomposed H₂O₂ to produce O₂, which could degrade HIF-1a to enhance the efficacy of tumor therapy. As shown in Fig. 6c, the DCFH-DA fluorescence image showed that the nanomaterial had the ability of SDT to produce ROS, and CAT could enhance the SDT effect. Meanwhile, the use of ultrasonic excitation compensated for the lack of penetration of light. In addition to CAT, Mn-based nanomaterials could also serve as a H₂O₂-responsive nanozyme for SDT.¹³⁹ For example, Zhu et al. designed a protoporphyrin-based nanoplatform that loaded into the hollow mesoporous organosilica nanoparticles (HMONs)-MnO_x to generate O₂ for enhancing SDT.¹⁴⁰

Fig. 6 (a) Schematic illustration of CSI@Ex-A nanoplatforms based on CAT and ICG for SDT. Reproduced from ref. 138 copyright 2022, Wiley-VCH GmbH. (b) HIF-1α fluorescence signals generated during different treatments. Reproduced from ref. 138 copyright 2022, Wiley-VCH GmbH. (c) ROS fluorescence signals generated during different treatments. Reproduced from ref. 138 copyright 2022, Wiley-VCH GmbH. (d) Schematic illustration of the synthetic process of Pt and apoptin-based nanoplatform and its mechanism of alleviating hypoxia and enhancing RT. Reproduced from ref. 141 copyright 2022, Wiley-VCH GmbH. (e) Schematic of PLGA-R837@CAT NPs to trigger ICD and anti-CTLA4 checkpoint blockade. Reproduced from ref. 64 copyright 2019, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

4.1.1.3 Enhanced radiotherapy and radiodynamic therapy. After X-ray irradiation, oxygen molecules can inhibit DNA repair and HIF-1 expression enhancing the effect of Radiotherapy.¹²⁹ Hypoxia can mitigate DNA damage as well as reduce the absorption of radiation, which makes the resistance of the tumor to RT.¹⁴² Hence, the rational design of nanomaterials for relieving hypoxia and enhancing tumor RT has been a hot area of research for several years. Zhou et al. reported a high-Z CeO₂-based nanoplatform for decomposing H₂O₂ to O₂ and enhancing RT.¹⁴³ The nanoplatform exhibited CAT-mimic activity, induced DNA damage and inhibited tumor growth. Similar nanoplatforms based on Pt NPs as CAT-like nanozymes have been designed for enhancing RT (Fig. 6d).¹⁴¹ This nanoplatform possessed pH-responsive property, worked as radiosensitizer and had CAT-like activity to improve radiotherapy sensitivity. Compared with no oxygen supply, this strategy highly enhanced the effect of RT. Not only that, Sun et al. presented the RDT mechanism based on the X-ray excitation that transformed O₂ to ¹O₂, combining the advantages of RT and PDT.¹⁴⁴
4.1.1.4 Enhanced immunotherapy. For immunotherapy of cancer, alleviated hypoxia environment can also be used to enhance their effect.¹⁴⁵ Some studies have been reported that the therapy effect could be weakened by hypoxic-mediated immune suppression.¹⁴⁶ Therefore, alleviating hypoxia to enhance immunotherapy is a feasible tumor treatment strategy. Chen et al. designed poly PLGA-R837@CAT nanoparticles to produce O₂ for increasing immunogenic cell death (ICD) and then combined with anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) checkpoint blockade (Fig. 6e).⁶⁴ This nanoparticle was based on the core–shell PLGA nanoparticle to load CAT for synergistic oncotherapy. The PLGA-R837@CAT nanoparticle could destruct primary cancers under X-ray radiation and trigger the immunogenic cell death. This study was mainly based on oxygen relieving immunosuppressive tumor microenvironment. Moreover, hypoxia has been reported to facilitate immune-supportive M1-type tumor-associated macrophages (TAM) to immune-suppressive M2-type TAM, which was a disadvantage for immunotherapy.¹⁴⁷ Therefore, the production of O₂ by decomposed H₂O₂ had also attracted tremendous attention for immunotherapy.

4.1.2 Enhanced tumor therapy by ˙OH production. In addition to producing oxygen, H₂O₂ can be used to produce ˙OH for tumor treatment. Chemodynamic therapy (CDT) is an emerging, minimally invasive, and effective cancer treatment, which is based on the H₂O₂ induce ˙OH formation via the Fenton or Fenton-like reaction.^10,148 Hydroxyl radical possesses efficient oxidative stress capacity for killing tumor cells.^149,150 Many nanomaterials have been reported that could be used for CDT, such as Fe-based, Mn-based, and other-based materials.^151–156 Fe-based materials have been widely used in the biological field because of their high biosafety.¹⁴⁸ The production of ˙OH could be induced by the reaction between Fe²⁺ and H₂O₂ in acidic environments.¹⁵⁷ Then, the ˙OH as a type of ROS could cause lipid peroxidation (LPO).¹⁰ Chen et al. designed unique amorphous iron nanoparticles (AFe NPs) which loaded with carbonic anhydrase IX inhibitor (CAI) for self-enhanced CDT based on the Fenton reaction (Fig. 7a).¹⁵⁸ The CAI could inhibit the expression of carbonic anhydrase IX, caused acidic ions to accumulate in the cell. The accumulated acidic ions could lower pH in cells and had an enhanced effect on CDT (Fig. 7b). Meanwhile, researchers found that Mn²⁺ and Cu²⁺ also have Fenton-like reaction.⁹² Inspired by this, Lin et al. synthesized MnO₂-coated mesoporous silica (MS) NPs to deplete GSH and produce ˙OH for CDT.¹⁵⁹ As depicted in Fig. 7c, the MnO₂ layer would release Mn²⁺, then the production of Mn²⁺ could react with H₂O₂ to generate ˙OH. As shown in Fig. 7d, the DCF fluorescence in tumor cells by MS@MnO₂ NPs was higher than MnCl₂ at the same Mn concentration. This proved that MS@MnO₂ NPs could produce stronger oxidative stress effects in the process of CDT. Hence, Fenton or Fenton-like reaction-based CDT has shown the great potential for cancer treatment.

Fig. 7 (a) Schematic illustration of AFe NPs for self-enhanced CDT. Reproduced from ref. 158 copyright 2019, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (b) The fluorescence images of DCFH-DA with different treatments. Reproduced from ref. 158 copyright 2019, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (c) Schematic illustration of MS@MnO₂ NPs to deplete GSH and produce ˙OH for CDT. Reproduced from ref. 159 copyright 2018, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (d) The fluorescence images of DCFH-DA with different treatments. Reproduced from ref. 159 copyright 2018, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

In addition, H₂O₂-related synergistic therapy based on glucose oxidase (GOx) or GOx-like nanomaterials that exhibited excellent properties, which often combined with other treatment methods for enhancing tumor therapy effect.¹⁶⁰ Chang et al. have designed a nanoplatform Cu₂MoS₄ for synergistic starvation therapy and CDT.²¹ Starvation treatment can continue to produce H₂O₂ to replace the H₂O₂ consumed by CDT. In other studies, H₂O₂-related gas therapy has also been reported.¹⁶¹ Therefore, H₂O₂-related therapy strategies play important roles in the research of tumor therapy.

4.1.3 Enhanced tumor therapy by H₂O₂-related imaging guidance. Currently, H₂O₂-related tumor imaging methods commonly used mainly include fluorescence imaging (FLI), magnetic resonance imaging (MRI), ultrasound imaging (USI), photoacoustic imaging (PAI), etc. Each of imaging strategies has its own advantage. For example, FLI is an emerging tumor molecular imaging method, which possesses the advantages of high spatial and temporal resolution.¹⁶² Overexpression of H₂O₂, a characteristic of TME, is widely believed to be involved in regulating the proliferation and malignant characteristics of cancer cells.³ Therefore, qualitative and quantitative research on H₂O₂ is conducive to understanding the progression of tumor development and judging the effect of related treatment. For instance, Yu et al. designed a lapachone-loaded H₂O₂-responsive nanoplatform to detect tumor by the H₂O₂-related chemiluminescence.¹⁶³
4.1.3.1 H₂O₂-related fluorescence imaging of tumor. In the field of biosensing, FLI can be used to detect the disorder of H₂O₂ in tumor.^164–170 The mechanism of H₂O₂-related FLI is mainly based on the fluorescence signal changes with the concentration of H₂O₂. For instance, Zhao et al. synthesized Cu ion-doped zeolitic imidazolate framework-8 (ZIF-8) loaded with AuNCs and DOX for FL imaging-guided therapy.¹⁷¹ When the pH decreased and H₂O₂ existed, DOX and Cu ions would be released, then fluorescence signals of DOX and AuNCs could be recovered. In other studies, a Janus nanoparticle Ag/Ag₂S Janus NP has been designed for the diagnosis of disease and detection of H₂O₂ by H₂O₂-activated NIR-fluorescence imaging.¹⁷² Due to the plasmonic electron transfer, the Janus NP possessed the ability of fluorescence quenching. The H₂O₂ served as a key to turn on the fluorescence signals under NIR irradiation in Fig. 8a. As shown in Fig. 8b, compared with the group without H₂O₂, the group with H₂O₂ showed strong fluorescence signals. Meanwhile, the fluorescence intensity increased with the increase of the contact time between nanomaterials and H₂O₂. Undoubtedly, the further exploration of FLI in biomedical applications will be readily pushed forward by these new probes for H₂O₂.

Fig. 8 (a) Schematic of Ag/Ag₂S Janus NPs for H₂O₂-activated NIR-fluorescence imaging. Reproduced from ref. 172 copyright 2021, American Chemical Society. (b) The change of fluorescence intensity under different conditions. Reproduced from ref. 172 copyright 2021, American Chemical Society. (c) Schematic illustration of ABTS for photoacoustic imaging. Reproduced from ref. 57 copyright 2019, American Chemical Society. (d) The change of PAI signal intensity. Reproduced from ref. 57 copyright 2019, American Chemical Society. (e) Schematic of nanoplatforms to continuously release oxygen bubbles for US imaging. Reproduced from ref. 180 copyright 2021, American Chemical Society. (f) The change of US intensity of in the tumor region. Reproduced from ref. 180 copyright 2021, American Chemical Society. (g) Schematic of AuNCs@mSiO₂@MnO₂ nanozymes for MRI. Reproduced from ref. 185 copyright 2021, American Chemical Society. (h) The change of MRI intensity of AuNCs@mSiO₂@MnO₂ nanozymes. Reproduced from ref. 185 copyright 2021, American Chemical Society.

4.1.3.2 H₂O₂-related photoacoustic imaging of tumor. Photoacoustic imaging (PAI) is also a promising diagnostic strategy that combines the advantages of traditional optical imaging and ultrasound imaging.¹⁷³ Briefly, a material undergoes thermoelastic expansion that is based on photothermal conversion under light irradiation, which is then converted to a US wave.¹⁷⁴ Some H₂O₂-responsive sensitizers possessed excellent properties for PA imaging, such as ABTS.⁴² Ding et al. designed a nanoplatform to load ABTS for PAI, which was based on the strong NIR absorbance of ABTS.⁵⁷ The mechanism was based on the HRP-catalyzed colorless ABTS substrate into its green oxidized form in the presence of H₂O₂ (Fig. 8c and d). According to the change of PA signals, the fluctuation in H₂O₂ concentration could be analyzed. Hence, PA imaging can also become an important method for disease diagnosis and H₂O₂ detection in the biomedical application.
4.1.3.3 H₂O₂-related ultrasound imaging of tumor. Ultrasound imaging is an important tool in biomedical imaging fields due to its high resolution, non-invasive method, and real-time modality.^175,176 Recently, many researches have reported to focus on contrast agents based on nanomaterials to produce gas bubbles in the tumor regions.^177,178 The generating bubbles could effectively reflect ultrasound signals, which were used for USI.¹⁷⁹ Wu et al. designed a nanosystem, which incorporated CAT and lactate oxidase (LOX), for enhancing US signals.¹⁸⁰ As shown in Fig. 8e, this nanoplatform could continuously release oxygen bubbles for USI by cascade catalysis of LOX and CAT. The continuously releasing oxygen bubbles could accumulate in the tumor region, which enhanced the specificity and continuity of USI (Fig. 8f). Thus, the generation of O₂ and the alleviation of hypoxia could be monitored. Besides, owing to its strong acoustic impedance, H₂O₂-induced CO bubbles could also serve as a contrast agent for USI.¹⁸¹
4.1.3.4 H₂O₂-related magnetic resonance imaging of tumor. Magnetic resonance imaging, a commonly used diagnostic tool, has the characteristics of high resolution, security, signal-to-noise ratio, and so on.¹⁸² MnO₂ has been found that it could decompose H₂O₂ into water and oxygen, and release Mn²⁺ ions by itself.¹⁸³ The non-lanthanide metal ion Mn²⁺ could short the longitudinal relaxation time (T₁) and transverse relaxation time (T₂) of water protons, thus enhancing T₁-magnetic resonance imaging contrast and weakening T₂-magnetic resonance imaging contrast.¹⁸⁴ As shown in Fig. 8g, Yin and coworkers used this feature to design a H₂O₂-responsive nanozyme (AuNCs@mSiO₂@MnO₂) for enhancing MR signals.¹⁸⁵ Herein, according to the change of MR signals, the concentration of H₂O₂ could be analyzed in Fig. 8h.
4.1.3.5 H₂O₂-related multimodal imaging of tumor. H₂O₂-related multimodal imaging can combine the advantages of different imaging modalities.¹⁸⁶ For instance, Wang et al. designed a new type of phthalocyanine manganese (MnPcE4) photosensitizer to achieve trimodal imaging (in vivo FL/CT/MRI).¹⁸⁷ Fluorescence imaging showed that the nanomaterial was able to rapidly accumulate in the tumor area. Furthermore, in the presence of H₂O₂, the Mn²⁺ could release as well as be used for MR imaging. The complementary advantages of different imaging models greatly improved the application of H₂O₂-related imaging.

4.2 Bacterial infections therapy by producing ROS and correlated imaging

It has been demonstrated that H₂O₂ is also overexpressed in the microenvironment of bacterial infection regions.⁸ Infections and unsuccessful wound healing caused by bacteria are among the serious health problems.¹⁸⁸ Utilizing H₂O₂ for producing ROS is an excellent antibacterial therapy.³¹ This is because ROS destroy the bacterial membrane and damaged DNA, leading to bacterial death.¹⁸⁹

As with tumor treatment, H₂O₂-related antibacterial therapy mainly includes PDT, SDT, and CDT.^190–192 As described in Fig. 9a, Hu et al. designed a phenylboronic acid-based nanozyme for antibacterial PDT.⁸ Sun et al. synthesized a Pd@Pt-T790 therapeutic nanoplatform with organic sonosensitizer meso-tetra(4-carboxyphenyl)porphine (T790) for bacterial therapy (Fig. 9b).¹⁹¹ The nanoplatform catalyzed H₂O₂ to produce O₂ and converted it into ROS under US irradiation. As shown in Fig. 9c, the results of colony counting showed that Pd@Pt-T790 nanoplatforms had good antibacterial effect of SDT. Moreover, H₂O₂ could be also used to directly generate ˙OH for antibacterial therapy.¹⁹² For example, Yang et al. designed Cu₂O nanoparticles, which catalyzed H₂O₂ to ˙OH by a Fenton-like reaction (Fig. 9d).¹⁹³ The oxidative stress caused by ˙OH could induce bacterial death. Then, Cu₂O nanoparticles could be transformed to Cu₉S₈ NPs in bacterial environment, which as photoacoustic agents accurately distinguished between bacterial infections and normal tissues (Fig. 9e). After injection of Cu₂O NPs, photoacoustic signal in normal tissue did not change significantly. However, Cu₂O NPs could be vulcanized to form Cu₉S₈ NPs in the infected tissue, the PA signal intensity reached the maximum after in situ injection at 12 h.

Fig. 9 (a) Schematic illustration of a phenylboronic acid-based nanozyme for synergistic antibacterial therapy. Reproduced from ref. 8 copyright 2021, Elsevier B.V. (b) Schematic illustration of a Pd@Pt-T790 nanotherapeutic platform for SDT. Reproduced from ref. 191 copyright 2020, American Chemical Society. (c) MRSA colony pictures after different treatments. Reproduced from ref. 191 copyright 2020, American Chemical Society. (d) Schematic illustration of Cu₂O nanoparticles for PA imaging-guided therapy. Reproduced from ref. 193 copyright 2021, Elsevier Ltd. (e) The PAI images of Cu₂O NPs in vivo at different time. Reproduced from ref. 193 copyright 2021, Elsevier Ltd. (f) Schematic illustration of Ce6@Arg-ADP for antibacterial therapy. Reproduced from ref. 33 copyright 2021, Wiley-VCH GmbH. (g) CLSM images of NO, ROS, and H₂O₂ generation in MRSA after different treatments. Reproduced from ref. 33 copyright 2021, Wiley-VCH GmbH. (h) Representative images of plate samples of E. coli and MRSA after different treatments. Reproduced from ref. 33 copyright 2021, Wiley-VCH GmbH. (i) Wound healing and colony change in vivo. Reproduced from ref. 33 copyright 2021, Wiley-VCH GmbH.

Similar to ˙OH, nitric oxide (NO) as a broad-spectrum antibacterial molecule could also be used for antibacterial therapy.¹⁹⁴ In the presence of H₂O₂, L-arginine could be oxidized to produce NO.¹⁹⁴ Zhu et al. designed a nanoplatform Ce6@Arg-ADP, which had rich L-arginine, to deal with bacteria.³³ The PDT could control generation of NO in situ and substantially promoted wound healing (Fig. 9f). As shown in Fig. 9g, there was almost no NO produced in PBS + laser-, Ce6@Arg-ADP-, Ce6 + laser-, Ce6@Lys-ADP + laser-treated bacteria, but large amount of NO was observed in Ce6@Arg-ADP + laser-treated bacteria. As displayed in Fig. 9h, at all tested concentrations, the antibacterial effect of Ce6@Arg-ADP + laser was significantly higher than that of Ce6 + laser and Ce6@Lys-ADP + laser. In the treatment of abscess, it was necessary to control infection, promote the rapid healing of disfigured wound, shorten the time of wound care, and avoid secondary infection. The result in Fig. 9i, Ce6@Arg-ADP + laser could inhibit bacterial infection and promote wound healing. Consequently, H₂O₂-based antibacterial treatment and imaging strategies provide an excellent method for further biomedical application.

4.3 Dental diseases therapy by producing ROS and correlated diagnosis

Dental microbial biofilms, which can embed microorganisms, are the causative factor of dental diseases, such as dental caries and periodontitis.^195,196 Because the entire biofilm is protected by a homegrown organic polymer matrix, it is more resistant to treatment than free bacteria.¹⁹⁶ Previously, ˙OH generation from H₂O₂ could disrupt dental microbial biofilms were reported.¹⁹⁶ Therefore, H₂O₂-related dental disease treatment and diagnosis receive more attention. For instance, Villa et al. synthesized self-propelled tubular microrobots to disrupt biofilms by the generation of bubbles and ˙OH (Fig. 10a).¹⁹⁶ As shown in Fig. 10b, the motion mechanism was the decomposition of H₂O₂ into O₂ catalyzed by Pt NPs on the inner surface. Then, this caused O₂ exit from one end of the tube, which triggers its motion in the opposite direction. At the same time, it was not difficult to find from Fig. 10c that microrobots motion velocity was increased with the increase of H₂O₂ concentration. Thus, the self-propelled tubular microrobot could destroy biofilms in the presence of H₂O₂. Huang et al. designed Dex-IONP-GOx nanoplatforms to generate ˙OH from H₂O₂ for disrupting biofilms.¹³ As shown in Fig. 10d, this nanoplatform had cascade catalysis activity to continuously produce H₂O₂ and ˙OH for the prevention of dental caries. Furthermore, this study found that the Dex-IONP-GOx nanoplatform had specific binding to S. mutans, which has destructive effect on biofilm (Fig. 10e). Therapeutic effect evaluation of dental disease has also been developed recently.¹⁹⁷ Wang et al. designed copper oxide nanoparticles anchoring onto black phosphorus nanosheets for assessment of disease progression and treatment effectiveness.¹⁹⁷ This nanoplatform possessed superior selectivity, it could utilize human gingival crevicular fluid and saliva samples for the diagnosis of periodontitis.

Fig. 10 (a) Schematic illustration of self-propelled tubular microrobots to disrupt biofilms. Reproduced from ref. 196 copyright 2020, Elsevier. (b) Snapshot images of TiO₂/Pt microrobots moving in different solution. Reproduced from ref. 196 copyright 2020, Elsevier. (c) Speed of the TiO₂/Pt microrobots at different concentrations of H₂O₂. Reproduced from ref. 196 copyright 2020, Elsevier. (d) Schematic illustration of Dex-IONP-GOx nanoplatforms for prevention of dental caries. Reproduced from ref. 13 copyright 2021, Elsevier Ltd. (e) Fluorescence images of survival of different bacteria. Reproduced from ref. 13 copyright 2021, Elsevier Ltd.

4.4 Enhanced therapy and imaging by direct consumption of H₂O₂

4.4.1 Inflammations therapy and correlated imaging. Inflammation plays a pathological basis role in multiple chronic diseases.³⁴ Previous studies have shown that H₂O₂ can be produced in inflammation areas and kill infiltrating pathogens.³⁴ However, oxidative stress caused by excess H₂O₂ will exacerbate the inflammatory response and impede the repair of tissues and organs.¹⁹⁸ Oxidative stress of H₂O₂ damages endothelial barrier, promotes migration and infiltration of inflammatory cells, and aggravates tissue damage.¹⁹⁹ Therefore, the reduction of H₂O₂ is one of the effective ways for anti-inflammatory treatment. For example, Yim et al. designed two-dimensional (2D) transition-metal dichalcogenides (2D-TMD), which could scavenge intracellular H₂O₂ for inflammatory treatment (Fig. 11a).³² As described in Fig. 11b, the nanomaterial had a good ability to clear ROS and reactive nitrogen species (RNS), which could alleviate the inflammatory response to a large extent. Additionally, a H₂O₂-responsive nanoplatforms which released drugs and CO₂ gas treatment for inflammation inhibition have been reported.²⁰⁰

Fig. 11 (a) Schematic illustration of two-dimensional transition-metal dichalcogenides for inflammatory treatment. Reproduced from ref. 32 copyright 2020, American Chemical Society. (b) The clearing of ROS and RNS by 2D-TMD. Reproduced from ref. 32 copyright 2020, American Chemical Society. (c) Schematic illustration of Au–Pd@Ag nanorods for detection of H₂O₂ by PA imaging. Reproduced from ref. 34 copyright 2020, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (d) PA intensity of 700 nm and 1260 nm at different hydrogen peroxide concentrations. Reproduced from ref. 34 copyright 2020, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

More than that, imaging can be used to assess changes in H₂O₂ concentration in the inflamed area, enabling monitoring of therapeutic effects and inflammatory progression.^201,202 Li et al. designed a novel nanotheranostic agent (TMSN@PM) to scavenge the excess ROS for alleviating inflammation and release Mn²⁺ ions.²⁰³ The number of Mn²⁺ ions released was correlated with the ROS level, which could be monitored by MRI. Moreover, Ye et al. designed a H₂O₂-responsive nanomaterial (Au–Pd@Ag nanorod) to detect H₂O₂ by PAI (Fig. 11c).³⁴ The PAI signal at 1260 nm and 700 nm could be used accurately differentiate the inflammation region and normal tissue in Fig. 11d. In another study, a nanoparticle that could be responsive to H₂O₂ to produce CO₂ bubbles for USI has been developed.²⁰⁴ And a Co complex has been designed for detection of H₂O₂ production by MRI.²⁰⁵ Utilizing the large change in chemical shift shown at ¹⁹F when oxidizing from Co(II) to Co(III), this was done using a chemical shift selective pulse train. Furthermore, H₂O₂-responsive nanomaterials have also been shown to be useful in the treatment and diagnosis of other inflammatory diseases, including inflammation of musculoskeletal systems, interstitial cystitis, ulcerative colitis, lupus nephritis, etc.^{176,206–208} In a word, H₂O₂-responsive nanomaterials offer an alternative strategy for inflammation therapy and diagnosis.

4.4.2 Cardiovascular diseases therapy and correlated imaging. In the cardiovascular system, H₂O₂-responsive nanomaterials can be used for the treatment and imaging of many diseases, such as thrombosis.²¹³ Myocardial infarction (MI), a cardiac disease, has a high mortality rate in the world.²¹⁴ A hypoxic microenvironment in MI tissues will induce aberrant production of H₂O₂.²¹⁵ Unfortunately, excessive H₂O₂ will lead to myocardial damage, which is adverse to cardiac repair after MI.²⁰⁹ Therefore, scavenging of H₂O₂ and production of O₂ means a potential way for MI repair. Ding et al. synthesized a hydrogel, that contained CAT, to turn H₂O₂ into O₂.²⁰⁹ As depicted in Fig. 12a, this hydrogel possessed excellent properties to scavenge H₂O₂ for MI repair. Experimental results showed that removing H₂O₂ was beneficial to MI repair. Moreover, cardiac hypertrophy is also associated with H₂O₂, which is caused by MI, leading to cardiac failure.^216,217 Inspired by this, a nanofiber has been developed to scavenge H₂O₂ for cardiac hypertrophy inhibition as shown in Fig. 12b.²¹⁰ In addition, H₂O₂-related nanotechnology could also be used for early cardiac disease diagnosis, such as early acute myocardial infarction.²¹⁸

Fig. 12 (a) Schematic illustration of hydrogel for H₂O₂-scavenging and O₂ generating. Reproduced from ref. 209 copyright 2020, Wiley-VCH GmbH. (b) Schematic illustration of nanofiber for mitigating H₂O₂ generated after myocardial infarction. Reproduced from ref. 210 copyright 2020, Elsevier B.V. (c) Schematic illustration of Fu-sBR nanoassemblies for antithrombotic treatment. Reproduced from ref. 211 copyright 2021, Wiley-VCH GmbH. (d) Fluorescence images of thrombosed IVC excised at 60 min after injection. Reproduced from ref. 211 copyright 2021, Wiley-VCH GmbH. (e) Photographs of thrombosed IVC excised at 48 h after the release of ligation. Reproduced from ref. 211 copyright 2021, Wiley-VCH GmbH. (f) Schematic illustration of nanoprobe to detect H₂O₂ for atherosclerotic plaque vulnerability assessment. Reproduced from ref. 212 copyright 2019, American Chemical Society. (g):PA imaging of BSA-Cy-Mito nanoprobe with different concentrations of H₂O₂ and GSH. Reproduced from ref. 212 copyright 2019, American Chemical Society.

Similarly, H₂O₂-related nanotechnology has been widely used in vascular systems, such as thrombus and angiogenesis.^219,220 It has been reported that the pathophysiological process of thrombus is associated with H₂O₂.^221,222 The generation of H₂O₂ was associated with activated platelets and injured endothelium.²²³ Platelet-dependent thrombus formation could be progressed by high levels of H₂O₂.²²⁴ Herein, the removal of overproduced H₂O₂ was an effective method for thrombosis treatment. Jung et al. synthesized H₂O₂-responsive Fu-sBR nano assemblies to scavenge H₂O₂ (Fig. 12c).²¹¹ This nanomaterial possessed the ability for targeted on-demand treatment of thrombus. As shown in Fig. 12d and e, due to the H₂O₂-responsive effect of Fu-sBR, there was no attenuation of the fluorescence signal within 60 min. However, sBR was not H₂O₂-responsive effect, and the fluorescence signal continued to decay. Photographs of thrombosed excised at 48 h, Fu-sBR had a good effect on the treatment of thrombus. In another study, Gao et al. designed a nanoprobe to detect H₂O₂ for atherosclerotic plaque vulnerability assessment by PAI and precise treatment in Fig. 12f.²¹² As described in Fig. 12g, the PAI signal of nanoprobe increased with the increase of H₂O₂ concentration. Furthermore, the H₂O₂-responsive nanoplatform has been proven to release drugs in the blood vessels.^{223,225–227} Therefore, these H₂O₂-related nanoplatforms offered excellent opportunities for future cardiovascular disease applications.

4.4.3 Bone injury therapy and correlated imaging. High ROS levels, a character of bone tissue injury, can promote osteoclast generation.²²⁸ H₂O₂, as a representative type of ROS, can induce oxidative stress, which is detrimental to bone injury repair.²²⁹ Therefore, nanotechnology to remove H₂O₂ provides a potential method for treatment of bone injury.

Lin et al. synthesized a Pt/CeO₂ nanozyme for the treatment of monosodium urate (MSU)-induced acute gout.²³⁰ As shown in Fig. 13a, nanosized Pt as a uricase and CAT mimic could scavenge uric acid and H₂O₂. The Pt/CeO₂ nanozyme catalyzed uric acid and O₂ to H₂O₂ and water-soluble allantoin, which reduced the production of the tophus. Then, the CAT mimic could provide a constant supply of oxygen, which creates a cycle of uric acid removal. Thus, the nanozyme alleviated joint pain and tissue injury. According to previous researches, peroxalate ester linkage was reported that it could also to react with H₂O₂.²³¹ Inspired by this, peroxalate ester-based PUDCA NPs have been synthesized to scavenge H₂O₂ and release ursodeoxycholic acid (UDCA) for promoting the osteogenic differentiation of mesenchymal stem cells (MSCs).⁵ As described in Fig. 13b, UDCA could be released in the presence of H₂O₂, followed by it scavenged H₂O₂ for bone tissue regeneration. This research also proved that reducing levels of H₂O₂ could decrease the adipogenic differentiation of MSCs, and then reduce the inhibition of bone regeneration. By micro-computed tomography analysis, PUDCA NP-treated group had the best effect on bone injury repair in Fig. 13c. In a similar study, Zhang et al. focused on improving the activity of MSCs and osteogenic differentiation.²³² Fe₃O₄@GO/BMP2 magnetic nanocomposites could reduce H₂O₂ by Fenton reaction and capture ˙OH for bone tissue regeneration under magnetic regulation.

Fig. 13 (a) Schematic illustration of synthesis and nanozyme activities of Pt/CeO₂ for treatment of acute gout. Reproduced from ref. 230 copyright 2022, American Chemical Society. (b) Schematic illustration of PUDCA NPs for bone tissue regeneration. Reproduced from ref. 5 copyright 2020, Elsevier B.V. (c) CT images after different treatments. Reproduced from ref. 5 copyright 2020, Elsevier B.V. (d) Schematic illustration of Lipo@HRP&ABTS nanoprobes for PAI. Reproduced from ref. 234 copyright 2021, Wiley-VCH GmbH. (e) The PA signal of Lipo@HRP&ABTS nanoprobes to detect H₂O₂. Reproduced from ref. 234 copyright 2021, Wiley-VCH GmbH.

More than that, H₂O₂-responsive nanomaterials have been proven to promote osteogenesis.²³³ Because of this, Li et al. designed hollow manganese dioxide nanoparticles (hMNPs)/gelatin methacryloyl (GelMA) composite hydrogels to clear H₂O₂ and release Mn²⁺ for promoting bone regeneration.²³⁴ MnO₂ NPs released Mn²⁺ in response to H₂O₂, and then Mn²⁺ promoted cell growth and osteogenic differentiation. In order to further study the concentration of H₂O₂ in the bone injury area, Lipo@HRP&ABTS nanoprobe was introduced in this experiment (Fig. 13d). In the presence of H₂O₂, Lipo@HRP&ABTS nanoprobe had strong NIR absorption, which could be converted into PA signal, realizing real-time imaging monitoring of H₂O₂ (Fig. 13e). In a word, H₂O₂-related nanoparticles had marvelous prospects in the treatment and diagnosis of bone injury.

4.4.4 Neurologic diseases therapy and correlated imaging. H₂O₂-induced cellular oxidation was not conducive to neurologic injury repair caused by diseases, such as neuroinflammation, traumatic brain injury, Parkinson's disease, and ischemic stroke.^{30,36,235,236} The production of H₂O₂ was related to reperfusion after ischemia stroke, and the oxidative stress generated by H₂O₂ would further aggravate the severity of ischemia stroke.²³⁷ According to previous researches, scavenging excessive H₂O₂ could effectively retard the progression of neuronal death caused by an ischemic stroke.²³⁷ Inspired by this, Li et al. designed a macrophage-disguised fingolimod (FTY)-loaded MnO₂ nanoparticles (Ma@(MnO₂ + FTY)) nanoparticle to convert H₂O₂ to O₂ in the ischemic brain.²³⁸ As depicted in Fig. 14a, the nanoparticle could polarity M1 type microglia (proinflammatory type) to M2 type (anti-inflammatory), then cooperated with decomposing H₂O₂ and generating O₂ to protect damaged neurons. As described in Fig. 14b and c, Ma@(MnO₂ + FTY) NPs could remove H₂O₂ while producing O₂, which was important for the protection of nerve cells. And oxygen-glucose deprivation/reoxidation (OGD/R) mimicked neuronal ischemia-reperfusion, demonstrating that ROS could be removed as a major source of nerve damage (Fig. 14d). Subsequently, [(Ru(dpp)₃)]Cl₂ probe was used to study the intracellular O₂ concentration, which proved that Ma@(MnO₂ + FTY) NPs could also produce a large amount of O₂ in the cell (Fig. 14e). Immunofluorescence results showed that OGD/R increased the expression of M1 marker CD16/32, and FTY and Ma@MnO₂ nanoparticles could decrease the expression of CD16/32 and increase the expression of M2 marker CD206 (Fig. 14f). Because it was a significant molecule in neurologic injury repair, change in H₂O₂ levels was closely related to the progression of diseases.²³⁹ Wang et al. designed a nanoprobe based on a PCAB for detecting H₂O₂ in vivo.²⁴⁰ A fluorescent imaging probe CRANAD-88 has been created to investigate H₂O₂ in Alzheimer's disease (AD) brains.²⁴¹ Qiao et al. have also done some research on H₂O₂-responsive nanomaterials for the treatment of AD.²⁴² Therefore, H₂O₂-related treatment and diagnosis have shown potential methods for neurologic diseases.

Fig. 14 (a) Schematic illustration of Ma@(MnO₂ + FTY) nanoparticles to protect damaged neurons. (b) The concentration of H₂O₂ with different concentration of MnO₂. (c) The concentration of O₂ with different concentration of MnO₂. (d) Scheme of the mechanism of neuroprotection by Ma@MnO₂ nanospheres on OGD/R. (e) Fluorescence images of intracellular oxygen concentration after different treatments. (f) Immunostained images of microglia with CD16/32 and CD206. (g) Quantification of the relative fluorescence intensity of CD206 versus CD16/32. (a–g) Reproduced under terms of the CC-BY license.²³⁸ Copyright 2021, C. Li et al., Published by Wiley-VCH GmbH.

4.4.5 Ophthalmic diseases therapy. It has been proved that some ophthalmic diseases were related to the increasing levels of H₂O₂.²⁴³ In ocular diseases, the overexpress production of H₂O₂ was based the prooxidative/antioxidative cellular imbalance.²⁴³ The overexpress production of H₂O₂ could disrupt retinal homeostasis, which is one of the cause of uveitis.³⁵ Not only that, the human eye is more susceptible to oxidative damage, especially to the cornea, because of its exposure to environment.²⁴⁴ As the ocular surface composition, antioxidative damage of cornea is an essential content for the treatment of ophthalmic diseases.²⁴⁴ Therefore, Choi and coworkers designed a ROS-scavenging ceria nanoparticle-embedded contact lens (CeNP-CLs) for scavenging the ROS on the cornea.²⁴⁵ As reflected in Fig. 15a, CeNP-CLs possessed CAT-like ability and SOD-mimetic activities, which could remove H₂O₂ and other ROS. With the increase of Ce concentration, the concentration of H₂O₂ continued to decrease (Fig. 15b). Corneal endothelial damage caused by H₂O₂ infiltration will lead to corneal opacity. As described in Fig. 15c, obvious corneal opacity could be found in the group with 0 mM CeNP-CLs after 3 days of H₂O₂ exposure, compared with before H₂O₂ exposure. According to the tissue sections, the degree of corneal epithelial injury in the group wearing 0 mM CeNP-CLs (Fig. 15d) was greater than that in the group wearing 50 mM CeNP-CLs (Fig. 15e). These findings suggested that adequate clearance of H₂O₂ in the presence of CeNPs-CLs can reduce damage to corneal epithelium and endothelial cells. To sum up, H₂O₂-related nanoparticles have marvelous prospects and potential in the treatment and diagnosis of many diseases.

Fig. 15 (a) Schematic illustration of CeNP-CL for scavenging the ROS on the cornea (b) changes of H₂O₂ at different Ce concentrations. (c) Representative photographs of the ocular surface for different groups. (d) Histologic photographs for the group wearing 0 mM CeNP-CLs. (e) Histologic photographs for the group wearing 50 mM CeNP-CLs. Reproduced from ref. 245 copyright 2020, American Chemical Society.

5 Conclusion and perspective

H₂O₂-responsive nanomaterials with their applications have been proven as interesting and meaningful methods for disease diagnosis and therapy. On the one hand, under external light or US excitation, the O₂ generated from the decomposition of H₂O₂ by the H₂O₂-responsive nanomaterials is converted into ROS for disease treatment. Hypoxia could also be alleviated by the generation of O₂, which enhanced the effectiveness of therapy. On the other hand, H₂O₂-responsive nanomaterials can catalyze H₂O₂ into ˙OH by Fenton or Fenton-like reaction. Furthermore, the combination of multiple treatments has also become a hot research topic. Treatment is often used in conjunction with other treatment modalities for increasing the effect, which possessed a “1 + 1 > 2” treatment effect. More importantly, imaging-guided therapy has been reported to could monitor the effect of H₂O₂-related treatments in real-time. This is mainly based on the fact that nanomaterials can react with H₂O₂ and enhance imaging signal. In this review, we summarized recent advances in H₂O₂-responsive nanomaterials and their applications in treatment and diagnosis of multiple types of diseases, including tumors, bacterium, dental diseases, inflammations, cardiovascular diseases, bones, neurologic diseases and ophthalmic diseases. According to the mechanism of therapy, they can be divided into two different groups: (1) producing ROS and (2) consuming H₂O₂.

Despite some advantages of H₂O₂-responsive nanomaterials and their related diagnosis and treatment approaches, many challenges are still needed to be addressed. (1) Most H₂O₂-responsive sensitizers or nanomaterials possess potential toxicity; (2) the synthesis process of H₂O₂-responsive nanomaterials is tedious and complex; (3) the researches on H₂O₂-related nontumor diseases therapy are not in-depth and comprehensive enough; (4) the effectiveness of some nanoplatforms still needs further improvement.

As a novel and versatile theranostic modality, H₂O₂-responsive nanomaterials have shown their high specificity and therapeutic performances in various biomedical applications, opening up new avenues for the treatment and diagnosis of H₂O₂ overexpression diseases. Provided the above challenges are adequately addressed, this unique H₂O₂-responsive nanomaterial is expected to enter the clinical stage in the near future to bring benefit to personalized biomedicine. Therefore, we hope that this review can contribute to providing new design inspirations and application ideas for various functional nanomaterials related to H₂O₂.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We gratefully acknowledge support from the National Natural Science Foundation of China (No. 82102056) and the Natural Science Foundation of Fujian Province of China (No. 2022J01280).

Notes and references

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