Functional metal nanozyme-hydrogel for biomedical applications

Precious metal nanozymes

Precious metal nanozymes such as gold (Au), platinum (Pt), palladium (Pd), and ruthenium (Ru) have become widely studied nanozyme systems due to their tunable catalytic activity, high chemical stability, and excellent electronic conductivity^[25]. Pt-based nanozymes (such as Pt NPs and Pt-Cu alloys) typically exhibit strong CAT and SOD-like activity, effectively decomposing H₂O₂ into H₂O and O₂, thereby alleviating tissue hypoxia and oxidative damage^[26]. Au nanozymes are promising antioxidants that have been proven to effectively eliminate ROS in the tumor microenvironment^[27].

It is worth noting that ruthenium-based nanozymes exhibit multi-enzyme-like activity and can form a cascade catalytic reaction, thereby achieving therapeutic effects on tumors^[28]. Lin et al. constructed multi-enzyme ruthenium nanozyme-hydrogels. In this system, Ru⁰/Ru⁴⁺ nanozymes are covalently embedded into the methylpropenylated gelatin network. Ru⁰ is responsible for adsorbing and removing NO, while Ru⁴⁺ exhibits excellent catalytic activity in ROS removal [Figure 2A]^[29]. However, despite the excellent catalytic performance of noble metal nanozymes, their low clearance rate and potential accumulation in circulation and tissues remain the main challenges in long-term biosafety studies^[30].

Figure 2. Engineering strategies and functional mechanisms of metallic nanozymes in metal nanozyme-hydrogel systems. (A) Noble Metal Nanozyme: Schematic illustration of the RuNZs’ multienzymatic activities, highlighting NO adsorption at Ru⁰ sites and ROS scavenging mediated by Ru⁴⁺ centers. Reproduced with permission from Ref.^[29]. Copyright 2024, Wiley; (B) Metal Oxide Nanozyme: Schematic representation of the ROS-scavenging performance of F/Rgel. Reproduced with permission from Ref.^[33]. Copyright 2025, Nature; Figure 2B is reproduced from (Zhang, F., 2025) under the CC BY-NC-ND license. No modifications were made; (C) Bio-Hybrid Nanozyme: Schematic illustration of the preparation of Mito-Fenozyme. Reproduced with permission from Ref.^[34]. Copyright 2021, Wiley; (D) Metal-Organic Framework: Schematic illustration of the preparation of the MOF. Reproduced with permission from Ref.^[45]. Copyright 2022, American Chemical Society; (E) Single-Atom Nanozyme: Illustration depicting the synthesis process of Fe_SA@FibBLG. Reproduced with permission from Ref.^[47]. Copyright 2024, Nature. ROS: Reactive oxygen species; MOF: metal-organic framework; Fe_SA@FibBLG: single-iron atom-anchored amyloid hydrogel catalytic platform based on β -lactoglobulin self-assembled fibers; NZs: nanozymes; CAT: catalase; SOD: superoxide dismutase; FTn: ferritin; TPP: triphenylphosphonium; DMF: N,N-dimethylformamide; BLG: β-lactoglobulin; FibBLG: nitrogen-rich site fiber structure; HRP: horseradish peroxidase.

Transition metal oxide nanozymes

Transition metal oxide nanozymes have attracted much attention due to their reversible multivalent state transformation and good biological metabolic compatibility. For instance, CeO₂ nanozymes can achieve self-regenerative redox catalysis through adjustable valence states (Ce³⁺/Ce⁴⁺ cycles), thereby maintaining ROS clearance capacity and antioxidant homeostasis for a long time^[31,32]. The Zhang team developed a dynamic phase regulation ε -polylysine-CeO₂ complex hydrogel (εPL-CeO₂ F/R gel), which achieves programmed regulation of the infection and repair phases through a Schiff base dynamic cross-linking network^[33]. This system utilizes the reversible electron transfer of Ce³⁺/Ce⁴⁺ of CeO₂ nanozyme to rapidly eliminate excessive ROS (including H₂O₂, •OH and O₂^•-, etc.) as shown in Figure 2B, significantly alleviating the oxidative stress-inflammatory cycle and restoring the homeostasis of the wound microenvironment. CeO₂ nanozyme simultaneously possesses CAT-like activity, capable of decomposing endogenous H₂O₂ into O₂, thereby alleviating hypoxia.

In addition, Zhang et al. constructed mitochondrial-targeted hybrid nanozymes (Mito-Fenozyme) using biomimetic strategies, which also achieved the functionalization of transition metal oxide systems^[34]. This platform uses ferritin (FTn) heavy chain as the protein scaffold, generates MnO₂ nanoclusters in situ through H₂O₂ oxidation of Mn²⁺, and then achieves mitochondrial-specific localization, as shown in Figure 2C. The obtained Mito-Fenozyme has dual enzyme activities of SOD and CAT, and can achieve the cascade transformation from O₂^•- to H₂O₂ and then to O₂ within cells, significantly reducing mitochondrial oxidative damage during myocardial ischemia-reperfusion. These studies indicate that the catalysis of transition metal oxide nanozymes depends on the valence state transition of metals and the structure of crystal defects. They can not only achieve continuous antioxidation through cycles such as Ce³⁺/Ce⁴⁺ or Mn⁴⁺/Mn^2+[34], but also realize microenvironment adaptive response by combining with intelligent hydrogel networks. Their excellent biocompatibility and ion metabolism characteristics make them have broad application potential in anti-inflammatory, anti-tumor and other aspects.

Prussian blue and metal-organic frameworks

Prussian blue is a clinically approved ferricyanide complex with inherent CAT, SOD and POD-like activities, which can effectively eliminate various ROS and alleviate inflammatory responses^[35,36]. For instance, Prussian blue nanozymes (PB NZs) can effectively reduce ROS levels and inhibit the expression of inflammatory factors in ischemia-reperfusion models^[35], and it also has good biocompatibility and safety. In addition, through ion doping (such as Zn, Mn, Cu, Co, etc.) or surface functionalization, its multi-enzyme cascade activity and specific targeting ability can be further enhanced^[37].

In contrast, MOFs are a typical class of porous nanomaterials, composed of organic linkers and metal ions^[38-40], and have become an ideal platform for constructing artificial enzymes due to their high specific surface area, inherent porosity and highly programmable chemical environment^[41,42]. Its unsaturated metal nodes can serve as catalytically active centers, while the functionalized organic ligands and the adjustable pore structure jointly create an efficient and selective reaction microenvironment, which greatly promotes substrate diffusion and electron transfer^[43,44]. Against this backdrop, a team designed a MOF-818 nanozyme/hydrogel system (MOF/Gel) with antioxidant oxidase mimicking activity based on the antioxidant properties of the metal-organic framework MOF-818^[45]. This system takes the MOF-818 constructed with Zn²⁺/Cu²⁺ coordination nodes and organic ligands as the core, and is in situ synthesized at 100 °C to form a highly crystallized octahedral structure. Its metal center simultaneously exhibits SOD-like and CAT-like activities. On the one hand, it catalyzes the disproportionation of O₂^•- to generate H₂O₂; on the other hand, it decomposes H₂O₂ to generate O₂ and H₂O, thereby achieving dual-channel clearance of ROS [Figure 2D]. In the chronic wound model of diabetes, MOF/Gel can continuously regulate the local oxidative stress level and promote the natural transition from the inflammatory phase to the proliferative phase.

Other novel nanozymes

In recent years, in order to achieve highly selective catalysis like enzymes, the design of novel nanozymes with clear active center structures has become a research hotspot. Among them, SANs and High-Entropy Nanozymes (HEzymes) offer two highly promising strategies. On the one hand, SANs have a clear geometric structure and highly dispersed active sites, making it an ideal model system^[46]. For instance, researchers constructed a single-iron atom-anchored amyloid hydrogel catalytic platform based on β -lactoglobulin self-assembled fibers (Fe_SA@FibBLG)^[47]. This system was prepared by a simple wet chemical impregnation method, β-lactoglobulin (BLG) self-assembled at high temperature (90 °C, 5 h) under acidic conditions to form a nitrogen-rich site fiber structure (FibBLG), and then Fe³⁺ ions were introduced to coordinate with nitrogen atoms to form Fe-N₄ active centers [Figure 2E]. This single-atom coordination structure features a stable and uniform electronic distribution, which can effectively simulate the catalytic characteristics of the active center. Animal experiments have shown that after oral administration, the blood alcohol concentration of mice decreased by 55.8% within 300 min, and no acetaldehyde accumulation or liver damage was caused, verifying its excellent biocompatibility^[47]. On the other hand, unlike SANs, which enhance selectivity through structural refinement, HEzymes adopt a different strategy, that is, they utilize the complex active interfaces and synergistic interactions composed of multi-metal components to improve catalytic performance. For instance, a study prepared FePtCoNiCu HEzymes by the low-temperature oil phase method and embedded them in a hydrogel matrix to construct a portable and low-cost on-site visual biosensing platform^[48]. This type of HEzymes also exhibits strong POD-like activity and can generate hydroxyl radicals by efficiently converting H₂O₂. Density functional theory calculations show that the strong electronic coupling among its various metal components promotes charge transfer through the D-orbital rearrangement near the Fermi level, thereby significantly improving the catalytic efficiency. Furthermore, HEzymes was fixed in alginate saline gel and combined with smartphone imaging to construct a portable, rapid and visual on-site colorimetric platform, which can be used for sensitive biological monitoring (such as biothiols, acetylcholinesterase, etc.).

The above-mentioned nanozymes each have their unique catalytic advantages and application limitations. Noble metal nanozymes (Au, Pt) typically exhibit high catalytic activity and stability, but the long-term bioaccumulation caused by their high cost and non-degradability is the main obstacle to their clinical transformation. Transition metal oxides (CeO₂, MnO₂) have shown great potential in the fields of antioxidants and anti-inflammation (such as wound repair) due to their excellent biocompatibility, controllable multivalent cycling and metabolizability^[49]. However, their catalytic activity is usually weaker than that of precious metals and is easily affected by local pH and H₂O₂ concentrations. MOFs and PB analogues offer highly configurable platforms. Their high porosity makes them easy to load other drugs, but their structural stability is a key issue that requires fine regulation. Their stability in the physiological environment is insufficient, and they degrade too quickly. SANs and HEzymes achieve high atomic utilization rate and natural enzyme-like catalytic mechanisms through well-defined active sites and synergistic electron effects, making them ideal models for mechanism research. However, their complex preparation processes and high costs limit their large-scale application.

Therefore, in practical applications, the selection of nanozymes is not about pursuing a single strongest activity, but should be based on a comprehensive consideration of specific scenarios, for instance, acute and short-term antibacterial applications may place more emphasis on catalytic efficiency (such as Pt)^[50]; For the long-term regulation of chronic inflammation, priority should be given to biological safety and metabolizability.

Dynamic catalysis of metal nanozymes

With the integration of energy science and materials science, the design of nanozymes has gradually expanded from static catalysis to energy-driven synergistic catalysis systems. By introducing exogenous energy fields such as photothermal (PTT) and photodynamic (PDT), dynamic intervention of the pathological microenvironment can be achieved while regulating the reaction rate and selectivity^[51-54]. Recently, Zhang’s team reported an intelligent conductive hydrogel (HEPP) system with multi-responsiveness and anti-inflammatory properties^[55]. This hydrogel triggers the release of embedded nanozymes (PTPPG) through the microenvironment, and simultaneously combines the self-cascading regulatory mechanisms of PDT, PTT and ROS to achieve multi-dimensional therapeutic functions. Specifically, PTPPG nanozymes possess activities such as CAT and POD, and can generate thermal and excited-state oxygen through the PDT/PTT effect under light (808 nm), rapidly eliminating pathogens^[55]. Meanwhile, its CAT-like activity can decompose H₂O₂ and continuously release oxygen, effectively alleviating the hypoxia state that is widespread in diabetic wounds.

Enhancing substrate accessibility

Substrate accessibility represents a core determinant of nanozyme catalytic efficiency, and free nanozymes often suffer from limited mass transport, aggregation-induced active-site shielding, and high diffusion resistance in physiological environments^[64]. Hydrogels address these limitations by constructing ordered, porous microenvironments that facilitate substrate transport and active-site exposure^[65].

Li et al. developed a structured hydrogel (TCH) incorporating the porous organic cage RCC1 for the treatment of fungal keratitis^[66]. TCH was formed via condensation between RCC1 and oxidized gellan gum, whose porous architecture creates interconnected channels that reduce diffusion resistance for substrates present in bodily fluids or corneal tissue fluid. This design enables efficient substrate delivery to nanozyme active sites, directly enhancing substrate accessibility. Moreover, the synergistic combination of the RCC1 cage-like motif and the hydrogel 3D network firmly immobilizes and uniformly disperses nanozymes, avoiding aggregation commonly observed in free nanozyme systems. Through spatial confinement, the RCC1-based hydrogel ensures full exposure of nanozyme active sites, fundamentally strengthening substrate-active site contact efficiency and boosting overall catalytic performance.

Responsive release and prolonged in vivo retention

A key advantage of hydrogel-nanozyme systems is spatiotemporal control over nanozyme distribution, which improves local bioavailability, extends therapeutic windows, and reduces off-target toxicity. Responsive hydrogels sense pathological microenvironmental cues to achieve on-demand degradation and controlled nanozyme release, thereby prolonging in vivo retention at target sites^[67].

A research team developed a glucose /H₂O₂ dual-responsive sound-sensitive hydrogel in response to the characteristic of difficult healing of implant infections in diabetic patients^[68]. This system uses carboxyphenylboronic acid (PBA) modified chitosan (CS-PBA) as the skeleton. After activation, it forms a borate ester cross-linked network with polyvinyl alcohol (PVA) as shown in Figure 3A. Endow the hydrogel with dual sensitivity to glucose and H₂O₂. This hydrogel can dynamically degrade and release MnO₂ nanozymes and sonosensitists in a high-sugar and high-oxidation environment. Under the action of ultrasound, it triggers the sonodynamic effect, generating ROS to kill bacteria and release antigens. Meanwhile, Mn²⁺ promotes the maturation of dendritic cells and activates the systemic immune response. This design fully demonstrates the unique advantages of the combination of hydrogel materials and nanozymes in immune regulation and antibioticfree antiinfective therapy achieved via responsive release and prolonged in vivo retention.

Figure 3. Design and fabrication strategies of hydrogel matrices in metal nanozyme–hydrogel systems. (A) Schematic illustration of the fabrication process of the CPA hydrogel. Reproduced with permission from Ref.^[68]. Copyright 2024, Elsevier; (B) The synthesis of the supramolecular hydrogel. Reproduced with permission from Ref.^[70]. Copyright 2025, Elsevier. CPA: Composite polymeric aquogel; PBA: phenylboronic acid; CS-PBA: carboxyphenylboronic acid modified chitosan; PVA: polyvinyl alcohol; BPQD@MOF: black phosphorus quantum dots@metal-organic framework; NCECS: nitrided chitosan.

Maintaining structural and catalytic stability

As a stabilizing carrier for nanozymes, hydrogels rely on network structural design and intermolecular interaction regulation to maintain nanozyme structural integrity and sustained catalytic activity^[69]. For nanozymes with multi-enzyme catalytic activities in particular, their stable catalytic function hinges on the dual stabilization of structure and activity provided by the hydrogel carrier.

The BPQD@MOF multi-enzyme cascade nanozyme hydrogel designed by Li et al. further validates the dual stabilization effects of hydrogel polymer matrices on nanozymes and their application potential in performance regulation^[70]. As illustrated in Figure 3B, this system, with PVA, agarose and nitrided chitosan (NCECS) as the main components, constructs a stable and self-healing bone repair matrix through a hierarchically organized hydrogen-bonding network. Strong hydrogen bonds (type I) form a skeletal support structure between NCECS, Agarose, and PVA, while reversible hydrogen bonds (type II) contribute to dynamic self-repairing behavior, and the BPQD@MOF nanozymes are stably immobilized within the hydrogel network through type III interactions with PVA segments, which prevents nanozyme aggregation, leaching and structural collapse at the microscopic level, thus achieving the microstructural stabilization of the nanozymes. Such a hierarchical hydrogen-bonding network not only imparts the material with outstanding mechanical flexibility and ductility, but also effectively maintains the catalytic stability of nanozymes via their stable immobilization and sustained controlled release, avoiding the attenuation of catalytic activity resulting from structural instability or premature release of nanozymes. This multi-network structure endows the material with excellent mechanical flexibility and ductility, and enables the continuous release of nanozymes. BPQD@MOF simultaneously possesses multi-enzyme activities such as PTT, glucose oxidation (GOx), and ROS clearance (SOD/CAT), achieving local glucose consumption, oxygen generation, and ROS clearance, thereby promoting M2 polarization and osteogenic regeneration of macrophages. Through the precise structural design of the hydrogel polymeric matrix, this system realizes the dual regulation of nanozymes’ structural stability and catalytic stability. It provides a multi-dimensional stabilized catalytic therapeutic strategy for diabetic bone defect repair, and further corroborates the core regulatory value of hydrogels in nanozyme stabilization applications.

Sustaining the redox cycle

Redox cycle is one of the core regulatory mechanisms for metal nanozyme-hydrogel systems to achieve long-acting and precise therapy. Hydrogels provide a confined, adaptive microenvironment that supports reversible metal valence transitions, accelerates electron transfer, and sustains closed-loop redox cycling for overcoming single-turnover catalytic limitations^[71,72].

Huang et al. established the FDPF thermosensitive hydrogel system centered on Fe-Co bimetallic nanozymes^[73]. This system constructs a closed-loop redox cycle through the dynamic valence state transitions of Fe²⁺/Fe³⁺ and Co²⁺/Co³⁺: H₂O₂ in the bacterial microenvironment binds to Co²⁺, triggering the oxidative transition of Co²⁺/Co³⁺ and driving the decomposition of H₂O₂ to generate •OH. Meanwhile, Co³⁺ is reduced back to Co²⁺ via electron transfer with Fe ions, and the synchronous valence state transition of Fe ions synergistically accelerates electron transfer to ensure the continuous operation of the cycle. The thermosensitive hydrogel forms a spatially confined network through gelation at 37 °C, stably immobilizing nanozymes to avoid aggregation or leakage of metal active sites. It also adapts to the acidic microenvironment of infected sites, providing favorable reaction conditions for valence state transitions. Combined with the photothermal effect of polydopamine (PDA) under 808 nm near-infrared (NIR) irradiation, the efficiency of electron transfer and cycle intensity are further enhanced. The •OH continuously produced by this redox cycle, synergistically with NO derived from D-Arg, achieves efficient treatment of subcutaneous abscesses and bacterial corneal ulcers. The hydrogel provides a suitable microenvironment for the valence cycle of metal nanozymes, breaks the limitation of single-turnover catalysis, continuously drives the redox cycle, and sustains the catalytic activity of nanozymes in the long term.

3D printing

3D printing technology features high flexibility and controllability^[74]. Through algorithm design and layer-by-layer addition of manufacturing techniques^[75], it enables the highly controllable construction of nanozymes and hydrogel precursors in space, providing programmable morphological and functional regulation capabilities for composite materials^[76-78].

For instance, Jin’s team developed an antioxidant nanozyme-hepatocyte spheroid 3D composite scaffold (HS/N-Au@composite) for the treatment of acute liver failure^[79]. The system prepared hyaluronic acid/gelatin/sodium alginate hydrogel loaded with NAC-modified gold nanoclusters (NAC-Au NCs) by 3D printing technology (N-Au@hydrogel) and combined with biological hydrogel-encapsulated hepatocyte spheroids containing acellular liver matrix (dECM), thrombin and fibrinogen (HS@dECM) [Figure 4A]. The obtained HS/N-Au@composite not only provides biomimetic mechanical support and cell adhesion microenvironment, but also significantly alleviates ROS-induced liver necrosis through the antioxidant and anti-inflammatory effects of Au nanozyme, promoting the functional recovery of transplanted cells and liver regeneration. This strategy has broken through the bottlenecks of low cell utilization and immune rejection in traditional liver transplantation, providing new ideas for stem cell therapy and organ regeneration.

Figure 4. Advanced manufacturing strategies for metal nanozyme-hydrogel systems. (A) Schematic illustration of the preparation of the HS/N-Au@ composite system for the treatment of acute liver failure. Reproduced with permission from Ref.^[79]. Copyright 2025, Elsevier; (B) Schematic representation of the surgical procedure. Reproduced with permission from Ref.^[80]. Copyright 2025, Elsevier; (C) Schematic illustration of the composition and formation mechanism of the oriented CuTA-CMHT hydrogel. Reproduced with permission from Ref.^[81]. Copyright 2024, Elsevier; Figure 4C is reproduced from (Dong, L., 2024) under the CC BY-NC-ND license. No modifications were made; (D) In situ injection of MS@MCL into a rat model to induce local lactate depletion and promote NP regeneration. Reproduced with permission from Ref.^[84]. Copyright 2022, Elsevier; Figure 4D is reproduced from (Shen, J., 2022) under the CC BY-NC-ND license. No modifications were made; (E) Fabrication and construction of the heterogeneous SponGel MS, which is inspired by the natural cartilage matrix. Reproduced with permission from Ref.^[85]. Copyright 2025, Wiley. CuTA-CMHT: Copper-tannic acid nanozyme and hyaluronic acid-tannic acid composite with carboxymethyl cellulose-methacrylate; MS@MCL: MnO₂-Chitosan-LOX (MCL) nanozyme was abundantly coupled to the porous microspheres via condensation reaction; NP: nanoparticle; SponGel MS: injectable chondroid heterogeneous biphasic microsphere; NAC: N-acetyl-L-cysteine; 3D: three-dimensional; hADMSCs: human adipose-derived mesenchymal stem cells; HLCs: hepatocyte-like cells; PDMS: polydimethylsiloxane; dECM: decellularized extracellular matrix; HS@dECM: hepatocyte spheroids@decellularized extracellular matrix; UV: ultraviolet; IVDD: intervertebral disc degeneration; NPCs: nucleus pulposus cells; SDF-1: stromal cell-derived factor 1; EGCG: epigallocatechin gallate.

Similar concepts have also been applied to the repair of intestinal defects and the treatment of corneal ulcers. For example, Su et al. prepared GDMA/Prussian Blue nanozyme wet adhesion hydrogel (GDMA@PB hydrogel) by 3D bioprinting^[80]. This material has both strong wet adhesion and immune regulation capabilities, and can closely adhere and achieve anti-inflammatory repair in intestinal perforation models, as shown in Figure 4B. Prussian Blue nanozyme endows it with SOD and CAT-like activities, promotes epithelial regeneration and alleviates tissue inflammation by inducing M2-type polarization of macrophages. Furthermore, the directional structure CuTA-CMHT hydrogel proposed by the Dong team utilized high-precision digital lithography (DLP) to achieve controllable manufacturing of micro-groove array structures, as shown in Figure 4C^[81]. This oriented hydrogel simulates the orthogonal arrangement of collagen fibers in the corneal stroma, significantly enhancing the cell adhesion, migration and orientation regeneration capabilities. The integrated CuTA nanozyme not only inhibits bacteria and eliminates ROS, but also regulates the TGF-β and NF-κB signaling pathways, thereby preventing scar formation and achieving functional corneal repair. These studies demonstrate that 3D printing technology can achieve precise macroscopic geometric construction and microscopic functional partitioning in nanozyme-hydrogel systems, providing the possibility for customized regeneration of complex tissues.

Injectable and in-situ gelation systems

For deep or complex geometric tissue injuries, injectable and in situ gel systems offer a minimally invasive and environmentally adaptive solution. Such systems are usually injected in the form of sols or microspheres and can achieve rapid gelation in vivo through temperature, pH, light or ion triggering, forming a 3D support network of adhesion without damaging the surrounding tissues^[60,82,83].

For instance, the Shen team constructed an MnO₂-lactate oxidase (LOX) nanozyme functionalized microsphere (MS@MCL) with injectable and long-lasting metabolic regulation capabilities^[84]. The system uses microfluidic technology (microfluidic fabrication) to prepare uniform-sized and pore-adjustable hyaluronic acid methacrylate (HAMA) microspheres as the matrix, achieving precise control of morphology, structure and rheological properties. A dynamic catalytic microreactor with both oxygen production and lactic acid consumption functions was constructed by firmly immobilizing MnO₂-LOX composite nanozyme on the surface of microspheres through chemical bonding. Thanks to the fluidity and plasticity endowed by microfluidic control, this material is in a fluid state before injection and can be directly injected into complex or narrow defect areas through fine needles. It rapidly disperses in the body and adheres to the interface of surrounding tissues, forming a uniformly distributed functional microenvironment as shown in Figure 4D. After injection, LOX catalyzes the oxidation of local lactic acid to pyruvate and H₂O₂, while MnO₂ further catalyzes the decomposition of H₂O₂ to produce O₂, thereby forming a lactic acid-oxygen self-circulation system, achieving long-term metabolic correction in an inflammatory microenvironment of hypoxia and high lactic acid.

Furthermore, Feng et al. developed an injectable chondroid heterogeneous biphasic microsphere (SponGel MS), whose unique structure simultaneously possesses flow injectability and in situ tissue shaping ability [Figure 4E]^[85]. This material is composed of a stable sponge-like scaffold phase and a dynamic hydrogel phase, among them, the hydrogel phase is cross-linked through Schiff base reaction, which can be gradually degraded in vivo and dynamically release MnO₂@EGCG nanozyme and chemokine SDF-1, thereby achieving continuous anti-inflammatory effect and stem cell recruitment after injection; The sponge phase is prepared through low-temperature free radical reactions, forming a support network with high porosity and mechanical toughness, providing a stable scaffold for cell adhesion, aggregation and cartilage differentiation. Thanks to its excellent injectable property, SponGel MS can directly fill complex-shaped cartilage defect sites through minimally invasive methods. In animal models, it effectively inhibits inflammatory responses (down-regulation of IL-1β and COL-1 expression) and promotes the regeneration and integration of hyaluronic cartilage, demonstrating significant application potential in cartilage tissue repair.

3D printing and injectable gels represent two distinct yet complementary clinical translational strategies. The core advantage of 3D printing (especially high-precision technologies such as DLP) lies in its unparalleled structural controllability, which enables the manufacturing of complex scaffolds with bionic microstructures (such as micro-grooves) and functional zoning^[86]. It is an ideal choice for achieving personalized customization of implants (such as corneal and cartilage scaffolds). However, its limitations lie in the fact that the manufacturing process is usually layer-by-layer and relatively slow, which imposes strict requirements on the rheological properties of bio-inks and has poor adaptability to deep or irregular tissue defects. In contrast, injectable in situ gel systems (such as microspheres and thermosensitive gels) have significant advantages of being minimally invasive, easy to operate, and capable of closely adhering to irregular defect shapes through flow, making them the preferred choice for treating deep tissue injuries (such as myocardial infarction and bone defect filling). However, the main challenge lies in the fact that the in-situ formed gel network usually has insufficient mechanical strength (such as stiffness and toughness), and its final morphology and internal pore structure are difficult to be precisely controlled in vivo. At the same time, the uncertainty of crosslinking degree before and after injection may lead to problems such as syringe blockage or precursor diffusion^[75]. In the future, synergistically integrating the two techniques could compensate for their respective limitations, thereby advancing the clinical translation of composite systems.

Hypoxia reversal and reactive ROS storm

Hypoxia is a prevalent characteristic of solid tumors, primarily caused by aberrant vasculature resulting from rapid tumor proliferation. This oxygen-deficient condition significantly compromises the efficacy of various therapeutic modalities, including radiotherapy and PDT^[93]. To address this limitation, hydrogels incorporated with metal-based nanozymes exhibiting CAT-like activity, such as copper selenide NPs or MOFs, can sustainably decompose endogenous H₂O₂ abundantly present in the TME to generate oxygen in situ, thereby effectively alleviating tumor hypoxia. This process not only directly enhances the outcomes of oxygen-dependent therapies like radiotherapy and PDT but also supplies molecular oxygen as a substrate for subsequent catalytic reactions. Furthermore, by co-loading nanozymes with POD-like activity within the same hydrogel system, chemotherapy-derived or exogenously supplied H₂O₂ can be utilized to initiate chemodynamic therapy (CDT), generating highly toxic hydroxyl radicals (•OH) that induce tumor cell death^[94-96].

To overcome the limitations posed by hypoxia in solid tumors, Li et al. devised a synthesis strategy utilizing hemin as a precursor to fabricate axially chlorinated single-atom Fe/N-doped carbon nanodots (Cl-FeNCDs) via a one-pot solvothermal approach^[97]. The resulting Cl-FeNCDs exhibit type I photodynamic properties, capable of efficiently generating superoxide anion radicals (O₂^•-) under 625 nm light irradiation even under hypoxic conditions. Notably, Cl-FeNCDs demonstrate a neutrophil-mimicking enzyme cascade functionality, encompassing SOD-, POD-, and myeloperoxidase-like activities. The photoinduced O₂^•- effectively triggers subsequent enzymatic cascades, addressing the constraint of substrate scarcity in oxygen-deprived tumor microenvironments. For efficient delivery, the team encapsulated Cl-FeNCDs into bovine serum albumin (BSA), forming biocompatible nanocomplexes (CDs@BSA), which were further incorporated into a photocrosslinkable and injectable hydrogel system. This hydrogel facilitates localized retention and activation within the postsurgical cavity, enabling effective suppression of triple-negative breast cancer (TNBC) recurrence through a topically applied, neutrophil-inspired photo-enzymatic cascade mechanism [Figure 5A]. In the postoperative triple-negative breast cancer model study, CDS@BSA-GEL was demonstrated to not only effectively eliminate residual tumor cells but also reverse the immunosuppressive microenvironment via immune stimulation triggered by immunogenic cell death (ICD), thereby significantly inhibiting tumor recurrence and prolonging survival. This strategy offers novel perspectives for oxygen-dependent anticancer therapies and paves the way for promising approaches in postoperative immunotherapy to prevent tumor recurrence, highlighting considerable potential for clinical translation [Figure 5B-D].

Figure 5. Tumor microenvironment remodeling and combination therapeutic strategies enabled by metal nanozyme-hydrogel systems. (A) Schematic Illustration of a Photoenzymatic Cascade Therapy (PECT): Carbon Nanodot-Based Hydrogel for Preventing Tumor Recurrence after Surgery; (B) Body weight, tumor volume, and survival curves after different treatments. ^****P < 0.0001; (C) Representative photographs of recurrent tumors after different treatments and H&E and TUNEL staining at the 24th day; (D) Timeline for treatment and recurrence monitoring following tumor resection. This figure quoted with permission from Ref.^[97]. Copyright 2025, American Chemical Society. Cl-FeNCDs: Axially chlorinated single-atom Fe/N-doped carbon nanodots; BSA: bovine serum albumin; CDs@BSA: encapsulation of Cl-FeNCDs in bovine serum albumin yields stable nanocomplexes; PDT: photodynamic; POD: peroxidase; MPO: myeloperoxidase; ROS: reactive oxygen species; GSDME: gasdermin E; CTL: cytotoxic T lymphocyte; DC: dendritic cell; DAMPs: damage-associated molecular patterns; + L: 625 nm light irradiation; H&E: Hematoxylin and Eosin; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling.

In a similar approach, Xu et al. developed an injectable self-healing hydrogel with pH-responsive properties, integrating gold NP-decorated titanium/iron bimetallic organic framework tetragonal nanosheets (Au/TF-MOF TNS) and the chemotherapeutic agent doxorubicin (DOX) for synergistic sonodynamic/chemo dynamic/starvation/chemo-therapy (SDT/CDT/ST/CT)^[95]. Under the acidic tumor microenvironment, the hydrogel enables controlled release of both Au/TF-MOF and DOX. Au/TF-MOF functioned as nanozymes, producing O₂ to alleviate tumor hypoxia, initiating the Fenton reaction to generate ∙OH for CDT, and depleting intracellular glucose to achieve starvation therapy. Furthermore, Au/TF-MOF acted as sonosensitizers, converting ambient O₂ into singlet oxygen (¹O₂) upon ultrasound irradiation, thereby elevating intracellular oxidative stress and triggering apoptosis. Both in vitro and in vivo antitumor studies demonstrated that the nanocomposite hydrogel effectively suppressed tumor growth and achieved highly efficient synergistic therapeutic outcomes.

Metabolic intervention and immune activation

High concentrations of GSH serve as vital antioxidants within tumor cells, efficiently scavenging therapy-induced ROS, and are a key factor in resistance to CDT and chemotherapy^[98]. Metal nanozymes with GSH-depleting capabilities [such as Cu-Fe₃O₄ nanoclusters (NCs), in which Fe²⁺ consumes GSH] can effectively disrupt the antioxidant defense system of tumor cells, thereby amplifying the ROS-mediated therapeutic effects. To achieve localized and sustained metabolic intervention within the tumor microenvironment, Zhang et al. dispersed Cu-Fe₃O₄ nanoclusters and artesunate (AS) into sodium alginate solution, followed by the addition of Ca²⁺ to induce the formation of a 3D porous network structure, constructing an injectable hydrogel capable of in situ stabilization^[99]. Delivery of Cu-Fe₃O₄ nanoclusters through the hydrogel enables localized and sustained release of Cu²⁺ and Fe²⁺/Fe³⁺. Intracellular accumulation of Fe²⁺ promotes lipid peroxidation and GSH depletion, ultimately leading to inactivation of GPx, impairing the cell’s ability to clear ROS and thereby initiating ferroptosis. DCFH-DA fluorescence staining demonstrated significantly elevated ROS levels in tumor cells treated with NCs, inducing mitochondrial membrane potential depolarization (JC-1), GSH depletion (ThiolTracker^TM Violet), and extensive apoptosis, as observed by a cell apoptosis staining kit (Annexin V-FITC/PI) and flow cytometry. In vivo experiments involved in situ injection of the hydrogel into a murine osteosarcoma model, which significantly inhibited tumor growth and prolonged mouse survival. Compared with the control group, the NCs-AS-ALG group showed a marked reduction in tumor volume and significantly improved survival rates^[99]. Histological staining (H&E, TUNEL, Ki67) revealed that the hydrogel could induce tumor cell apoptosis and inhibit proliferation. Immunofluorescence staining of tumor tissues further confirmed elevated ROS levels and activation of ferroptosis-associated molecular mechanisms in vivo, consistent with in vitro findings.

In addition to the direct tumoricidal effects achieved via CDT and chemotherapy, recent studies indicate that localized immunomodulation plays a pivotal role in enhancing antitumor responses^[100]. Miao et al. developed an injectable hydrogel (CFe/βCP+Cis hydrogel) with excellent tumor-site retention, controlled cisplatin release capability, and significant tumor immune microenvironment remodeling potential^[101]. The researchers co-dispersed porous single-atom iron-carbon nanozymes (CFe) and cisplatin into a β-CD-g-PEGMA (βCP) polymer brush hydrogel network^[101]. This system effectively reversed the immunosuppressive state by promoting the polarization of tumor-associated macrophages from the M2 phenotype to the M1 phenotype. Flow cytometry and immunohistochemistry results demonstrated a significant decrease in CD206⁺ (M2 marker) cell populations and an upregulation of CD86⁺ (M1 marker), while CD8⁺ cytotoxic T lymphocyte infiltration into the tumor was markedly enhanced, indicating activation of an adaptive immune response. Further investigations revealed that bone marrow-derived macrophages (BMDMs) treated with the CFe/βCP hydrogel secreted significantly elevated levels of proinflammatory cytokines such as TNF-α and IL-6^[101]. Moreover, their conditioned medium effectively inhibited tumor cell viability, suggesting that this material can mediate indirect antitumor effects via immune cell activation. To comprehensively evaluate the in vivo antitumor efficacy of the CFe/βCP+Cis hydrogel, the researchers established a subcutaneous CT26 tumor-bearing BALB/c mouse model^[101]. Fourteen days after initiation of treatment, a single local injection of the CFe/βCP+Cis hydrogel (Group G6) achieved sustained tumor growth inhibition. Compared with monotherapy groups receiving only CFe (Groups G3/G4) or the hydrogel matrix alone (Group G2), the CFe/βCP group (G5) exhibited significant tumor control, with a tumor inhibition rate as high as 68%, greatly exceeding that of the untreated group (G1) or single-agent control groups^[101].

Treatment strategies for infected diabetic wounds

Diabetes mellitus is a metabolic disorder characterized by elevated blood sugar levels^[102,103]. The healing of normal skin wounds goes through four stages in sequence: hemostasis, inflammation, proliferation and remodeling. However, in the diabetic state, this process is significantly hindered by the combined effect of persistent hyperglycemia, inflammatory imbalance and oxidative stress, resulting in typical chronic and difficult-to-heal wounds^[104]. The core pathology lies in the fact that immune dysregulation and oxidative damage-driven inflammation block the physiological transition to the proliferative phase^[105]. Therefore, the treatment strategy needs to be precisely intervened in stages according to the healing course to restore the homeostasis of the microenvironment and promote functional regeneration.

In the early stage of infection, inhibiting pathogen proliferation and eliminating excessive ROS are the keys to breaking the vicious cycle of inflammation^[4,106,107]. For instance, the Tu team designed a multifunctional MnO₂ nanozyme composite hydrogel (PPGA)^[108], which is composed of polyethylene glycol methacrylate - glycidyl methacrylate -acrylamide copolymer (PEGMA-GMA-AAm) cross-linked with highly branched polylysine-modified MnO₂ nanosheets. Further loading of pravastatin sodium to promote NO production. This system can simultaneously eliminate multiple ROS, continuously supply oxygen and release NO, achieving a synergistic effect of antibacterial, anti-inflammatory and immune regulation. In the diabetic skin wound model infected with methicillin-resistant Staphylococcus aureus (MRSA), PPGA significantly downregulated the levels of IL-1β, IL-6 and TNF-α, and induced macrophages to polarize to M2 type, thereby accelerating inflammation regression and tissue regeneration [Figure 6A]. Similarly, the zinc-based polymetallic oxonate nanozyme (Zn-POM)-based nanozyme functionalized hydrogel proposed by Pu et al. catalyzes the oxidation of glucose to gluconic acid and H₂O₂ through GOx, while Zn-POM acts as a CAT/SOD mimicase to further decompose H₂O₂ and eliminate ROS. Achieve precise intervention in the high-sugar microenvironment [Figure 6B]^[109].

Figure 6. Multifunctional treatment strategies for chronic infected wounds based on metal nanozyme-hydrogel systems. (A) An antibacterial hydrogel integrating ROS scavenging, O₂ generation and NO release eradicates MRSA infection, relieve inflammation and promotes healing in diabetic wounds. Reproduced with permission from Ref.^[108]. Copyright 2022, Elsevier; (B) Schematic diagram of producing H₂O₂ and scavenging ROS. Reproduced with permission from Ref.^[109]. Copyright 2024, Springer; Figure 6B is reproduced from (Pu, C., 2024) under the CC BY-NC-ND license. No modifications were made; (C) Schematic illustration of PdNPs extraction from the traditional Chinese medicine Bletilla striata, preparation of PDAs, and their subsequent microfluidic encapsulation into HAMA hydrogel microcarriers. Reproduced with permission from Ref.^[111]. Copyright 2025, Springer; Figure 6C is reproduced from (Che, J., 2024) under the CC BY-NC-ND license. No modifications were made; (D) PdNP + PDA@HAMA hydrogel microcarriers markedly enhance diabetic wound healing compared with controls, as evidenced by faster wound closure and improved histological regeneration on H&E and Masson’s staining (12 rats each group). Reproduced with permission from Ref.^[111]. Copyright 2025, Springer; Figure 6D is reproduced from (Che, J., 2024) under the CC BY-NC-ND license. No modifications were made; (E) Multifaceted functions of the MZGB hydrogel during diabetic wound healing. Reproduced with permission from Ref.^[112]. Copyright 2025, Elsevier; (F) Dynamic, phase-adaptive regulatory roles of the gel in promoting scarless wound healing. Reproduced with permission from Ref.^[33]. Copyright 2025, Nature. ROS: Reactive oxygen species; MRSA: methicillin-resistant Staphylococcus aureus; NPs: nanoparticles; PDAs: polydopamines; HAMA: hyaluronic acid methacrylate; H&E: Hematoxylin and Eosin; MZGB: Mn-ZIF@GOx/BC; HBPL: hyperbranched poly-L-lysine; PEGMA-GMA-AAm: polyethylene glycol methacrylate - glycidyl methacrylate -acrylamide copolymer; IL: interleukin; CXCL: Chemokine (C-X-C motif) ligand; TNF: tumor necrosis factor; CAT: catalase; SOD: superoxide dismutase; PBS: phosphate buffered saline; HE: Hematoxylin and Eosin; ATP: adenosine triphosphate; MCs: mast cells.

After the inflammation and oxidative stress of the wound are initially controlled, the treatment goal shifts to promoting a smooth transition from the inflammatory phase to the proliferative phase. The core of this stage lies in reshaping the immune microenvironment (such as inducing macrophage polarization) and providing support for cell proliferation^[45,110]. For instance, Che et al. used the extract of the traditional Chinese medicine Bletilla striata as a reducing agent and stabilizer to green synthesize active Pd NPs, and co-embedded them with PDA in HAMA hydrogel. The PdNP+PDA@HAMA complex microcarrier system [Figure 6C]^[111] was constructed. This system can effectively eliminate ROS, regulate the macrophage phenotype, restore fibroblast function, and has shown excellent pro-healing effects in animal experiments. In the full-thickness wound model of diabetes in mice, as shown in Figure 6D-i, compared with the PBS control group and the single group containing only HAMA, PdNP or PDA, the wound healing ability of PdNP+PDA@HAMA complex microvector was outstanding, and the healing rate on the 9th day was significantly better than that of PBS and the single component control [Figure 6D-ii]. Histological analysis revealed that HE staining showed that in the PdNP+PDA@HAMA group, granulation tissue was most closely connected to the surrounding skin, and regeneration was obvious; Mason tricolor staining further revealed that this group had the richest collagen deposition and orderly fiber arrangement, thereby accelerating tissue repair and improving the structure and function of the skin after healing [Figure 6D-iii]. In addition, some research teams have further combined redox homeostasis with mitochondrial function repair. For instance, the Yan team developed the Mn-ZIF@GOx/BC (MZGB) hydrogel system^[112]. This system uniformly disperses the Mn-ZIF@GOx (MZG) nanozyme with SOD/CAT cascade activity in the bacterial cellulose (BC) matrix, and forms a stable composite network through hydrogen bonds and electrostatic interactions. It utilizes glucose oxidation in the body to produce gluconic acid, reducing local pH, while decomposing excessive ROS and providing O₂, thereby achieving redox homeostasis and metabolic self-regulation, as shown in Figure 6E. MZGB not only restores mitochondrial function and ATP levels, but also promotes angiogenesis and epithelial regeneration by inducing M2-type polarization, and demonstrates ROS-independent antibacterial properties. Therefore, it collaboratively regulates immunity and redox homeostasis, significantly promoting angiogenesis and diabetic wound repair.

Ideal wound healing not only requires a fast speed but also the near-physiological recovery of function and appearance. The key lies in effectively inhibiting excessive fibrosis in the later stage of repair to prevent scar formation^[113]. Recently, the dynamic adaptive regulation of hydrogels (F/R gels) reported by Zhang et al. demonstrated a new direction for precise regulation in the late healing stage [Figure 6F]^[33]. This system forms a hierarchical drug release system through dynamic cross-linking of Schiff bases. Initially, ε-polylysine and CeO₂ nanozyme are released to fight bacteria and eliminate ROS. Subsequent remodeling of the growth and fibroblast subtypes effectively inhibits scar formation. In mouse and rabbit ear diabetic wound models, this system achieved rapid and scarless functional skin regeneration.

Internal environment-triggered nanozyme-hydrogels are used in treating bacterial infection wounds

Bacterial infections, especially chronic wounds that form biofilms, have significant differences in their internal microenvironment (such as pH value, concentrations of specific enzymes and metabolites) from normal tissues^[114]. The internal environment-responsive nanozyme-hydrogel designed on this basis can achieve precise and on-demand release of antibacterial drugs, thereby effectively eradicating infections and promoting tissue regeneration.

The key signaling molecules of the microenvironment of infected wounds provide multiple trigger targets for intelligent nanozyme-hydrogels. The main trigger types include pH response and microenvironmental-specific response, etc.^[115]. At the site of bacterial infection, the accumulation of metabolic products leads to changes in the local pH value, thereby causing alterations in the acidity or alkalinity of the environment^[116]. Therefore, pH response is the most common triggering mechanism. pH-responsive hydrogels can intelligently release nanozymes or change their structure and activity under the stimulation of the infected site to achieve the purpose of capturing and killing bacteria. For instance, a research team has constructed a MOF nanozyme composite cryogel (CSG-MX), in which Fe-MIL88NH2 nanozyme is grafted onto glycidyl methacrylate functionalized dialdehyde chitosan through Schiff base reaction^[117]. CSG-MX possesses high hydrophilicity, acid-enhanced positive charge, and pH-responsive nanozyme release and rebinding capabilities. Thanks to the negative potential of bacteria, the influence of infection on pH, and the pH-responsive reversible release and enzyme activity of nanozymes (such as POD and OXD mimicase activity), CSG-MX can achieve intelligent adaptive capture and killing of bacteria in the presence of low concentrations of H₂O₂ (100 μM) [Figure 7A].

Figure 7. Internal microenvironment-triggered metal nanozyme-hydrogel systems for antibacterial therapy and infected wound repair. (A) Schematic Diagram of CSG-MX preparation and its subsequent applications. Reproduced with permission from Ref.^[117]. Copyright 2021, American Chemical Society; (B) Schematic illustration of the underlying antibacterial mechanism. Reproduced with permission from Ref.^[118]. Copyright 2024, Oxford University Press; (C) Proposed mechanisms through which OBG@CG facilitates diabetic wound repair. Reproduced with permission from Ref.^[121]. Copyright 2024, Elsevier; (D) SEM images and live-dead images of bacteria after different treatments. Reproduced with permission from Ref.^[121]. Copyright 2024, Elsevier; (E) Mechanism illustration of CuCD1-based microenvironment responsive disruption of bacterial biofilm. Reproduced with permission from Ref.^[122]. Copyright 2025, Elsevier; (F) Tissue-regenerative effects of CPAN-AMP in infected diabetic wounds. Reproduced with permission from Ref.^[120]. Copyright 2025, Wiley. CSG-MX: Chitosan-based cryogel - MOF nanozyme composite; MOF: metal-organic framework; OBG@CG: OHA/borax-gelatin hydrogel@Cu_2-xSe-BSA-GOx; SEM: scanning electron microscopy; CPAN-AMP: conductive polyaniline-antimicrobial peptide composite hydrogel; POD: peroxidase; GSH: glutathione; HIF: hypoxia-inducible factor; VEGF: vascular endothelial growth factor; CS-GMA: chitosan-g-glycidyl methacrylate; APS: ammonium persulfate; TEMED: tetramethylethylenediamine; BLK: blank; Gox: glucose oxidase.

The more sophisticated design makes use of multiple signals in the infection microenvironment. For example, A programmed self-activating antibacterial hydrogel in response to bacteria has been developed. This system consists of pH-responsive H₂O₂ self-supplied complex nanozyme (MSCO) and pH/enzyme-sensitive LOX micelles jointly encapsulated in L-arginine-modified chitosan and phenylboronic acid-modified oxidized glucan hydrogels^[118]. In the infection microenvironment, bacterial metabolic products (such as lactic acid) cause a decrease in pH^[119]. On the one hand, this activates the protonation of the guanidine and amino groups of CA to destroy the bacterial cell wall. On the other hand, MSCO dissociates to release Cu²⁺ and H₂O₂. H₂O₂ mediates the Fenton reaction catalyzed by Cu²⁺ and the POD-like activity of MoS₂, efficiently generating •OH. Meanwhile, the LOX released by PPEL catalyzes the decomposition of lactic acid, generating more H₂O₂ and forming a positive feedback effect. Furthermore, H₂O₂ and Cu²⁺ also trigger the self-driven cascade release of NO, weakening the bacterial resistance to ROS [Figure 7B].

It is worth noting that biofilms are the core obstacle that makes chronic infections difficult to cure. Nanozymes-hydrogels triggered by the internal environment have shown great potential in destroying the structure of biofilms. In addition to the traditional pH value or enzyme sensitivity reaction systems, researchers have also developed smart materials that respond to metabolic signals in infectious wounds. The glucose activation mechanism is a typical representative among them. It directly utilizes the pathological feature of high glucose concentration in diabetic wounds to achieve disease-specific therapeutic regulation^[120]. For the variable microenvironment of infectious diabetic wounds, a study has constructed a double-dynamic bond cross-linked hydrogel (OBG@CG) loaded with GOx and pH-responsive self-assembled Cu_2-xSe-BSA nanozyme^[121]. In the acute infection period, acidic conditions trigger Cu_2-xSe-BSA nanozyme self-assembly, activate its POD-like activity, catalyze H₂O₂ to produce •OH, and efficiently attack bacterial biofilms [Figure 7C]. During the wound recovery period, when the pH value increases, Cu_2-xSe-BSA depolymerizes, terminating the production of ROS, and the released Cu²⁺ can promote collagen production and angiogenesis. The antibacterial effect of the material was confirmed by scanning electron microscopy (SEM) and live/dead staining images of bacteria. After treatment, the bacterial morphology was damaged and a large number of bacteria died [Figure 7D]. In addition, other response strategies targeting the biofilm microenvironment are equally effective. For instance, the Cu-doped carbon dot nanozyme (CuCD1) designed by researchers emphasizes responsive clearance of the bacterial biofilm microenvironment^[122]. This nanozyme features an ultra-small size and a positively charged surface, enabling it to penetrate biofilms in slightly acidic environments and catalyze the generation of endogenous H₂O₂ to •OH. This enhanced oxidative stress destroys the membrane structure of bacteria, achieving the eradication of biofilms [Figure 7E]. Researchers further loaded CuCD1 into carboxymethyl chitosan/oxidized glucan cross-linked hydrogels. This composite system can continuously kill bacteria and promote collagen deposition.

Furthermore, a recently reported glucose-activated programmable hydrogel (CPAN-AMP) with self-switching enzyme-like activity demonstrated the potential of metabolic signal-driven multimodal reaction systems in complex wound environments^[120]. This system consists of Au-MoS₂ -phenylboronic acid (PBA) nanozyme, nitroimidazole-modified sodium alginate microcapsules loaded with insulin and PBA-chitosan network. In hyperglycemia, CPAN-AMP oxidizes glucose to generate ROS for antibacterial action. The resulting hypoxia, together with nitroreductase and bioreductants, drives amphiphilic alginate to reduce nitroimidazole into hydrophilic aminoimidazole, disrupting capsule amphiphilicity and triggering insulin release. Under normoglycemia, CPAN-AMP switches to oxygen generation, preventing hypoxia-responsive capsule transformation and relieving tissue hypoxia. This programmable hydrogel enables feedback glycemic control and orderly wound repair [Figure 7F].

External environment-triggered nanozyme-hydrogels are used for the treatment of bacterial infection wounds

In addition to responding to the physiological signals on the wound surface, precisely manipulating the nanozyme-hydrogel system using external physical fields (such as light, heat, and sound) provides a powerful non-invasive treatment tool for addressing deep infections and biofilm issues. This external triggering strategy has outstanding advantages such as controllable time and space and adjustable dosage^[123,124]. The external stimuli applied to the treatment of bacterial infection wounds are mainly divided into two categories: NIR light and ultrasound.

Combining internal microenvironment responses with external stimuli can achieve more precise and efficient synergistic antibacterial treatment. For instance, a research team has developed an alginate (Alg/CuP) hydrogel based on copper hydrogen phosphate (CuP) nanozyme^[125]. This system ingeniously takes advantage of the pH differences among various wounds: in acidic infected wounds, it exhibits POD-like activity to produce •OH for bactericidal purposes; In alkaline diabetic wounds, it switches to CAT-like activity to produce oxygen and promote angiogenesis. Meanwhile, this hydrogel has excellent NIR photothermal conversion capability. The mild thermal effect produced by near-infrared light irradiation can significantly enhance its pH-responsive catalytic activity and Cu²⁺ release, thereby synergically accelerating the healing of various refractory wounds [Figure 8A].

Figure 8. External environment-triggered metal nanozyme-hydrogel systems for antibacterial therapy and infected wound healing. (A) Multifunctional, pH-switchable CuP nanozyme-composite alginate hydrogel exhibiting mild photothermal-enhanced catalytic activity and therapeutic ion release, significantly accelerating the healing of various refractory wounds. Reproduced with permission from Ref.^[125]. Copyright 2023, American Chemical Society; (B) Schematic illustration of the antibacterial effect of the hydrogel. Reproduced with permission from Ref.^[127]. Copyright 2023, Wiley; (C) Schematic illustration of a NIR-responsive nanozyme-hydrogel combines ROS generation, photothermal effects, antibacterial activity and antioxidation to promote healing of bacteria-infected wounds. Reproduced with permission from Ref.^[128]. Copyright 2025, Elsevier; (D) Schematic diagram of the MoS₂@TA/Fe NSs’ POD- and CAT-like activities. Reproduced with permission from Ref.^[131]. Copyright 2022, Elsevier; Figure 8D is reproduced from (Li, Y., 2022) under the CC BY-NC-ND license. No modifications were made; (E) Stimuli-responsive hydrogel dressings integrating bacterial-trapping, antimicrobial, and antibiofilm functions to accelerate wound healing. Reproduced with permission from Ref.^[132]. Copyright 2025, Elsevier; (F) The adhesion, rheological properties and microstructure of the hydrogel. Reproduced with permission from Ref.^[132]. Copyright 2025, Elsevier. NIR: Near-infrared; ROS: reactive oxygen species; NSs: nanozymes; POD: peroxidase; CAT: catalase; PTT: photothermal; bFGF: basic fibroblast growth factor; CDT: chemodynamic therapy; EGCG: epigallocatechin gallate; OD-AB: modified dextran; PDA: polydopamine; CMCS-PEI: carboxymethyl chitosan - polyethylenimine; OACPPIh: developed using OD-AB, CMCS-PEI, PDA, and iron-hydrated nanoparticles; NPs: nanoparticles.

The PTT can not only directly kill bacteria but also significantly enhance the catalytic efficiency of nanozymes^[126]. A study has constructed a PNMn hydrogel with multi-enzyme activities (POD, CAT, OXD) and excellent NIR-II photothermal performance. Its photothermal effect can enhance enzymatic catalytic reactions, thereby generating ROS more effectively^[127]. In addition, this hydrogel also has the property of bacterial capture, which can enrich bacteria in the ROS generation region and further enhance the antibacterial effect, as shown in Figure 8B. Similarly, a research team functionalized the injection of PVA-alginic acid hydrogel with Ag@MXene nanozyme^[128]. MXenes (transition metal carbides and nitrides) are a class of emerging two-dimensional materials^[129]. In this design, Ag nanoclusters not only provide more catalytically active sites but also efficiently convert NIR light energy into thermal energy. This photothermal-enhanced catalytic effect jointly constructs the NIR-responsive ROS generation antibacterial platform [Figure 8C].

The ideal nanozyme-hydrogel system should be capable of dynamically regulating ROS levels according to therapeutic needs: effectively generating ROS in the antibacterial stage and eliminating excessive ROS in the subsequent anti-inflammatory stage^[130]. Hydrogels based on tannic acid-metal-modified MoS₂ double nanozymes (MoS₂@TA/Fe NSs) have this function^[131]. Under acidic conditions, it generates ROS through POD-like activity; In a neutral environment, it switches to CAT-like activity, which can not only eliminate H₂O₂, but also produce oxygen [Figure 8D]. This bidirectional dynamic regulation ability of ROS levels enables it to adapt to the needs of different stages of wound healing.

In addition, for different clinical needs, good adhesion and mechanical adaptability of hydrogels are crucial for frequently moving parts such as joints. A team designed an intelligent stimulus-responsive hydrogel with glycocalyx-mimetic structure^[132]. This system functions through a sophisticated cascade reaction; it captures bacteria by taking advantage of the characteristics of the simulated glycocalyx-mimetic structure, and then, under NIR irradiation, the photothermal effect of PDA synergistically kills bacteria with cations. Meanwhile, the photothermal effect can also increase the CAT-like activity of hydrated iron nanozyme by eliminating ROS and producing oxygen [Figure 8E]. This hydrogel exhibits excellent tissue adhesion, can firmly adhere to pigskin and even the joints of moving hands, and can withstand compression and tensile deformation [Figure 8F]. Its self-healing property also ensures long-term stable coverage of dynamic wounds.

Ultrasound, as an external stimulus capable of penetrating deep tissues, features non-invasiveness and high penetration depth^[133-135]. Therefore, it is often used to activate photosensitizers for SDT. In response to the complex pathological features commonly present in diabetic infected wounds, such as hypoxia, high H₂O₂ (leading to oxidative stress), and biofilm barriers, researchers have developed a sophisticated ultrasound-responsive nanozyme-hydrogel system. For example, a team developed a multifunctional antibacterial hydrogel dressing (PPCN@Pt-AMPs/HGel) for treating diabetic infected wounds^[136]. The system was based on gelatin and sodium alginate, loaded with the nano-sonosensitizer PN-224, Pt nanozymes with CAT-like activity, and antimicrobial peptides (AMPs) targeting biofilms, as shown in Figure 9A. Under low-intensity ultrasound irradiation, this system exhibits a cascade effect of synergistic treatment; the CAT-like activity of Pt nanozyme catalyzes the decomposition of excess H₂O₂ in the wound bed into O₂. This process not only alleviates the oxidative stress of the wound, but more importantly, the O₂ produced, as a key substrate, greatly alleviates the hypoxic state of the wound bed, thereby significantly enhancing the SDT efficacy of the sonosensitized agent PCN-224 and enabling it to efficiently generate ROS to kill bacteria. Meanwhile, the biofilm-targeting ability of AMPs further assists in the clearance of infections. In MRSA-infected diabetic rat models, the PPCN@Pt-AMPs/HGel (US) treatment group showed the fastest wound healing rate and the highest healing quality [Figure 9B], confirming its significant effect in promoting wound healing in infectious diabetes.

Figure 9. Ultrasound-responsive metal nanozyme-hydrogel systems for enhanced antibacterial therapy and infected wound healing. (A) An ultrasound-activated PPCN@Pt-AMPs/HGel dressing alleviates H₂O₂-mediated oxidative stress and hypoxia while enhancing sonodynamic therapy to promote healing of diabetic-infected wounds. Reproduced with permission from Ref.^[136]. Copyright 2025, Elsevier; (B) Representative wound photographs at multiple time points and corresponding healing curves, illustrating residual wound area over time under different treatments (n = 3). US: with the ultrasound irradiation at 0.8 W/cm² for 5 min. WO: without ultrasound irradiation. ^*P < 0.05, ^***P < 0.001. Reproduced with permission from Ref.^[136]. Copyright 2025, Elsevier; (C) Schematic depiction of the preparation of GelMA + PNAs and their ultrasound-assisted wound healing mechanism. Reproduced with permission from Ref.^[137]. Copyright 2023, Royal Society of Chemistry; (D) Comparative analysis of wound healing-related mechanisms under different treatments, including (i) ROS levels, (ii) HIF-1α expression, (iii) EGF expression, and (iv) VEGF expression on day 6. Reproduced with permission from Ref.^[137]. Copyright 2023, Royal Society of Chemistry; (E) Schematic illustration of PNAs’ GR-like activity. Reproduced with permission from Ref.^[137]. Copyright 2023, Royal Society of Chemistry; (F) Quantitative assessment of ROS levels and HIF-1α, EGF, and VEGF expression on day 9 following different treatments. (n = 3 independent mice). ^**P < 0.01, ^***P < 0.001, ^****P < 0.0001. Reproduced with permission from Ref.^[137]. Copyright 2023, Royal Society of Chemistry. PPCN@Pt-AMPs/HGel: Polydopamine-Prussian blue nanocage loaded with platinum-antimicrobial peptides/hydrogel; AMPs: antimicrobial peptides; HGel: hydrogel; GelMA: gelatin methacryloyl; PNAs: platinum nanoparticle assemblies; ROS: reactive oxygen species; HIF: hypoxia-inducible factor; EGF: epidermal growth factor; VEGF: vascular endothelial growth factor; GR: glutathione reductase; PCN: porous coordination network; DA: dopamine; SDT: sonodynamic therapy; MRSA: methicillin-resistant Staphylococcus aureus; BHGel: biological hydrogel; US: ultrasound; WO: without ultrasound; POD: peroxidase; GSSG: oxidized glutathione; GSH: reduced glutathione; M1: M1 macrophage; M2: M2 macrophage; NADPH: nicotinamide adenine dinucleotide phosphate; NADP⁺: nicotinamide adenine dinucleotide phosphate (oxidized form); NPs: nanoparticles.

Another study developed a hydrogel based on platinum NP assemblies (PNAs) and revealed a new role of ultrasound in nanozyme catalysis^[137]. PNAs are high-density platinum NP assemblies synthesized using metal-organic coordination polymers with dynamic covalent bond hybridization as templates. Mechanistically, under the action of ultrasound, this system not only exhibits traditional CAT-like and POD-like activities to modulate ROS levels but also facilitates macrophage polarization from the pro-inflammatory M1 phenotype to the regenerative M2 phenotype [Figure 9C]. This metabolic reprogramming translates into enhanced tissue repair signals; specifically, immunofluorescence analysis revealed that the expressions of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) were significantly upregulated in the treated wounds, indicating effective promotion of angiogenesis and epithelialization [Figure 9D]. This therapeutic efficacy is fundamentally driven by a novel glutathione reductase (GR)-mimicking activity: ultrasound induces a surface plasmon resonance effect on dense Pt NPs, which promotes the electron transfer of coenzyme reduced coenzyme II (NADPH) and enables the catalytic reduction of oxidized GSH to reduced GSH [Figure 9E]. The regeneration of GSH is crucial for regulating cellular redox homeostasis. Ultimately, quantitative assessment confirmed that the GelMA + PNAs + US treatment effectively alleviated oxidative stress (reduced ROS and HIF-1α) while enhancing repair factors, achieving high-quality tissue repair [Figure 9F].

In conclusion, whether it is the internal stimulation of the wound microenvironment or the application of an external physical field, the core objective is to achieve on-demand and precise regulation of the functions of the nanozyme-hydrogel system (such as ROS generation/clearance, drug release, and O₂ supply). Internal stimuli (such as pH response) endow dressings with intelligent adaptive capabilities, enabling them to automatically activate antibacterial functions when infections occur and even switch their enzyme activity patterns at different pathological stages (such as hyperglycemia/hypoglycemia). External stimuli (such as light and sound) offer a higher level of active control and have superior controllability in terms of time and space. Through external triggering, not only can non-invasive treatment of deep tissues be achieved, but it can also be coordinated with internal responses, significantly enhancing the catalytic activity of pH responses through photothermal effects, or enhancing multi-enzyme synergistic antibacterial effects. The ideal smart dressing precisely integrates internal and external stimulus responses, ingeniously connecting the efficient antibacterial/anti-biofilm stage with the subsequent anti-inflammatory, antioxidant and pro-regeneration stages (such as promoting angiogenesis and collagen deposition), shifting from simple sterilization to the regulation of microenvironment homeostasis, thereby providing a more powerful and precise solution for the healing of chronic infected wounds.

Related to bone and joint

Although osteoarthritis (OA), rheumatoid arthritis (RA), and bone defects are respectively related to mechanical wear, immune abnormalities, and trauma/infection in terms of etiology, all three are accompanied by obvious inflammatory responses, inflammatory cell infiltration, and continuous destruction of osteochondral cartilage during the onset process. Excessive accumulation of ROS and abnormal upregulation of inflammatory factors are their common pathological driving forces. It directly leads to joint tissue damage, bone loss and functional degeneration^[12,138,139]. In recent years, the composite system of nanozymes and hydrogels has demonstrated unique advantages in reshaping the local microenvironment, promoting bone regeneration and delaying the progression of lesions due to its antioxidant, anti-inflammatory and sustained-release properties.

The multi-enzyme cascade activity of nanozymes can effectively eliminate excessive ROS in the lesion area, alleviate inflammatory responses, protect cells and tissues, and thereby regulate the microenvironment of bone regeneration^[140]. For instance, Wang et al. reported a therapeutic strategy based on manganese trioxide (Mn₃O₄) nanozymes for alleviating cartilage degeneration in OA^[141]. This nanozyme has multi-enzyme activities similar to those of SOD and CAT, which can effectively eliminate the accumulated ROS in the joint cavity, thereby reducing the damage of oxidative stress to chondrocytes and inhibiting inflammatory responses. To achieve local and persistent delivery, the research team embedded Mn₃O₄ nanozymes into injectable chondroitin sulfate (CS) hydrogels. In the medial meniscus instability surgery-induced OA mouse model, the Mn₃O₄@CS hydrogel treatment group demonstrated a significant cartilage protective effect. The Micro-CT image Figure 10A-i shows that the joint surface destruction and osteophyte formation in the treatment group were significantly improved. HE staining [Figure 10A-ii] confirmed the reduction of cartilage destruction and inflammatory cell infiltration, while fanred-O staining Figure 10A-iii showed that the cartilage thickness and integrity of the treatment group were effectively maintained, indicating that this composite system could significantly slow the progression of OA.

Figure 10. Anti-inflammatory and regenerative applications of metal nanozyme-hydrogel systems in bone and joint tissues. (A) Mn₃O₄@CS hydrogel alleviated cartilage degeneration in a mice model. (i) Representative micro-CT images for each group, and (ii) H&E and (iii) Safranin O staining used to evaluate cartilage degeneration. Reproduced with permission from Ref.^[141]. Copyright 2023, Wiley; (B) Schematic illustration of the fabrication of a DNA hydrogel co-loaded with MSC-derived mitochondria and nanozymes, and its application in RA therapy. Reproduced with permission from Ref.^[142]. Copyright 2025, Elsevier; Figure 10B is reproduced from (Wang, F., 2025) under the CC BY-NC-ND license. No modifications were made; (C) Schematic representation of the hydrogel platform designed for RA treatment. Reproduced with permission from Ref.^[144]. Copyright 2025, Nature; (D) Proposed mechanism of ROS scavenging by the DAGQD@Cu SAN. Reproduced with permission from Ref.^[144]. Copyright 2025, Nature; Figure 10D is reproduced from (He, H., 2025) under the CC BY-NC-ND license. No modifications were made; (E) (i) An anatomic illustration of hydrogel adhesion within the joint; (ii) FESEM and (iii) metallographic microscopy images of the hydrogel-cartilage cross-section. Reproduced with permission from Ref.^[144]. Copyright 2025, Nature. Figure 10E is reproduced from (He, H., 2025) under the CC BY-NC-ND license. No modifications were made. CS: Chondroitin sulfate; ROS: reactive oxygen species; SAN: single-atom nanozyme; CTL: control; DMM: destabilization of the medial meniscus; MSC: mesenchymal stem cell; RGD: Arg-Gly-Asp; RA: rheumatoid arthritis; IL: interleukin; TNF: tumor necrosis factor; M1: M1 macrophage; M2: M2 macrophage; iNOS: inducible nitric oxide synthase; CD206: cluster of differentiation 206; DA-HA: dopamine-modified hyaluronic acid; KGN: kartogenin; SOX9: SRY-box transcription factor 9; GQD: graphene quantum dot; CAT: catalase; PBS: phosphate buffered saline; DAGQD: dopamine-derived graphene quantum dot.

In the more complex microenvironment of RA, a single anti-inflammatory or antioxidant strategy is often insufficient to repair existing tissue damage. In response to this, Wang et al. designed a polymer-modified DNA hydrogel platform for the synergistic delivery of Prussian blue nanozyme and active mitochondria to achieve the dual goals of anti-inflammation and repair^[142]. This DNA hydrogel has excellent biocompatibility, injectability, self-healing and shear-thinning properties, making it suitable for intra-articular administration. In this system, Prussian blue nanozyme is responsible for eliminating excessive exogenous ROS in the RA microenvironment and down-regulating pro-inflammatory cytokines to alleviate the inflammatory response. Meanwhile, the delivered healthy mitochondria replenish the function of damaged cells through mitochondrial transfer, inhibit the production of endogenous ROS and restore cellular energy metabolism, as shown in Figure 10B. This strategy that combines eliminating exogenous sources with inhibiting endogenous sources has significantly promoted the proliferation of chondrocytes in animal experiments, alleviated RA symptoms, and repaired joint tissues.

In addition, in the bone immune microenvironment of RA, the efficacy of stem cell therapy is often limited by ROS and hypoxic stress. To address this challenge, Zhao’s team developed a nanozyme-enhanced self-repairing hydrogel as an H₂O₂ -driven Oxygenerator to reshape the RA microenvironment and improve osseointegration at the prosthesis interface^[143]. This system, with manganese cobalt oxide nanozyme as its core, can not only eliminate excessive ROS but also synergistically utilize endogenous H₂O₂ to generate dissolved oxygen, thereby alleviating local hypoxia and oxidative stress. As a delivery carrier of bone marrow mesenchymal stem cells, this hydrogel protects the implanted cells from ROS and hypoxia-mediated death, significantly enhances their osteogenic potential, and simultaneously downregulates local inflammatory factors, ultimately achieving better bone integration and arthritis relief.

In addition to anti-inflammatory and regenerative properties, hydrogels can also be endowed with lubricating functions to reduce joint friction, which is crucial for the treatment of OA and RA. For instance, He et al. developed an injectable bioadhesive and lubricating hydrogel for the full-cycle treatment of RA as shown in Figure 10C^[144]. The hydrogel is loaded with a multifunctional Cu single-atom nanozyme. This nanozyme efficiently eliminates various ROS such as H₂O₂ and •OH through a dual catalytic mechanism of Cu single atoms (providing SOD/ CAT-like activity) and the catechol-quinone redox pair of dopamine, as shown in Figure 10D, thereby effectively inhibiting the inflammatory microenvironment. In addition, hydrogels can continuously release chondroietin, recruit stem cells and promote their differentiation into chondrocytes to repair damaged cartilage. This design achieves lubrication and anti-inflammatory protection for early-stage RA to cartilage repair for advanced-stage RA, providing a highly promising full-cycle treatment strategy. This system consists of a dopamine-modified hyaluronic acid (DA-HA) and sulfonated hyaluronic acid (SO₃^--HA) network. Inspired by mussel adhesion proteins, DA endows the hydrogel with strong bioadhesion, enabling it to firmly adhere to the surface of articular cartilage [Figure 10E] for long-term retention. The SO₃^--HA network simulates the composition of synovial fluid, providing excellent lubricity and significantly reducing the coefficient of friction.

Intestinal-related

In recent years, the composite system of nanozymes and hydrogels has gradually become a potential strategy for the treatment of inflammatory bowel disease (IBD). Unlike the application in relatively closed joint cavities and fluid environments, the intestinal environment features acid-base gradients, digestive enzymes, food flow, and complex flora, making it extremely easy for drugs to be diluted or inactivated. Therefore, in IBD, in addition to providing in situ retention and sustained-release protection, it is also necessary to have certain oral stability, mucosal adhesion and inflammatory site targeting, so as to ensure the stability and local effective concentration of nanozym-hydrogel in the complex intestinal environment^[145-147].

During the course of IBD, nanozymes can effectively eliminate excessive ROS in the lesion area, reduce the levels of inflammatory factors, and alleviate oxidative stress and tissue damage. Specifically, the multi-enzyme activity of nanozymes can be administered through the rectum or orally, effectively eliminating excessive ROS in intestinal lesions, thereby blocking inflammatory signaling pathways and reducing tissue damage and apoptosis. For instance, the research team designed a thermosensitive hydrogel containing Mn₃O₄ nanozymes, which can target the inflamed colon^[148]. In the mouse colitis model, this composite system can form a gel in situ at the inflammatory site, continuously remove ROS, significantly reduce the levels of pro-inflammatory factors, and improve intestinal function^[148].

To enhance the retention and targeting efficiency of nanozyme in the intestinal tract, the excellent biocompatibility, injectability and sustained-release performance of hydrogels make them an ideal platform. Through sustained-release action, hydrogels can maintain the local concentration of nanozymes in the lesion area and prolong the therapeutic effect. For instance, Zhang et al. reported a complex system in which Mn₃O₄ nanozymes were immobilized on kaolin and further embedded into PDA hydrogels^[149]. The PDA coating enables the system to rapidly form adhesions in the colon and firmly remain in the damaged and inflamed areas with its strong mucosal adhesion, enhancing the efficiency of local retention and removal of ROS and restoring the expression of barrier-associated tight junction proteins.

Gut microbial species play an important role in host health^[150]. The occurrence of IBD is closely related to the imbalance of intestinal flora. Merely eliminating ROS is not enough. The hydrogel system that combines nanozyme with probiotics or specific inorganic components can not only reduce inflammation but also reshape the micro-ecological environment and promote the recovery of intestinal homeostasis. For example, Zhou et al. constructed a dual-targeted Mn@CeO₂ nanozyme-modified probiotic hydrogel microsphere (MnCe@LR/AMs)^[151]. In this study, Mn@CeO₂ nanozymes with high SOD and CAT-like activities were first coated on the surface of Lactobacillus reuteri, and then it was prepared by electrostatic spraying, which overcomes the gastrointestinal barrier [Figure 11A]. Sodium alginate facilitated dual targeting of MnCe@LR/AMs by combining charge-mediated interactions with mannose receptor-mediated binding at inflammation-associated regions [Figure 11B and C]. The negative charge of alginate enables it to electrostatically adsorb onto positively charged inflammatory mucosal areas. Meanwhile, the mannose residues in its structure can specifically bind to the highly expressed mannose receptors on macrophages at the inflammatory site. In the dextran sulfate sodium colitis model, MnCe@LR/AMs effectively repaired the intestinal barrier through the synergistic effect of nanozymes (ROS clearance) and probiotics (colonization), and improved immune homeostasis by regulating the polarization of macrophages from M1 type to M2 type. At the same time, it significantly increases the relative abundance of beneficial bacteria (such as Lactobacillus reuteri), improves amino acid metabolism, and thereby reshapes the intestinal microecology^[151].

Figure 11. Intestinal anti-inflammatory and regenerative applications of metal nanozyme-hydrogel systems. (A) Schematic illustration of a nanocoating-hydrogel microsphere system that enhances intestinal colonization of probiotics. Reproduced with permission from Ref.^[151]. Copyright 2025, American Chemical Society; Figure 11A is reproduced from (Zhou, P., 2025) under the CC BY-NC-ND license. No modifications were made; (B) Schematic diagram showing MnCe@LR/AMs targeting colonic inflammation via electrostatic adsorption and mannose receptor-mediated recognition. Reproduced with permission from Ref.^[151]. Copyright 2025, American Chemical Society; Figure 11B is reproduced from (Zhou, P., 2025) under the CC BY-NC-ND license. No modifications were made; (C) MnCe@LR/AMs derived from Mn@CeO₂ nanozymes tolerate gastric acid, target inflamed colonic sites, scavenge ROS, repair the intestinal barrier, and modulate gut microbiota, metabolism, and immune responses. Reproduced with permission from Ref.^[151]. Copyright 2025, American Chemical Society; Figure 11C is reproduced from (Zhou, P., 2025) under the CC BY-NC-ND license. No modifications were made; (D) Schematic illustration showing that W-PB gel treats IBD by efficiently scavenging ROS, alleviating inflammation, and modulating the gut microbiota. Reproduced with permission from Ref.^[152]. Copyright 2025, Elsevier; (E) Experimental flowchart of the treatment on IBD mice model. Reproduced with permission from Ref.^[152]. Copyright 2025, Elsevier; (F) H&E staining and AB/PAS histological staining. Reproduced with permission from Ref.^[152]. Copyright 2025, Elsevier. MnCe@LR/AMs: Dual-targeted Mn@CeO₂ nanozyme-modified probiotic hydrogel microsphere; ROS: reactive oxygen species; W-PB: tungsten-doped Prussian blue; IBD: inflammatory bowel disease; H&E: Hematoxylin and Eosin; AB: Alcian blue; PAS: periodic acid-Schiff; DSPE: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine; PEG: polyethylene glycol; LR: L. reuteri; ZO-1: Zonula occludens-1; CAT: catalase; IL: interleukin; TNF: tumor necrosis factor; M1: M1 macrophage; M2: M2 macrophage; IFN: interferon; DSS: dextran sulfate sodium; PB: Prussian blue; 5-ASA: 5-aminosalicylic acid.

Similarly, Luo et al. designed a tungsten-doped Prussian blue (W-PB) nanozyme and encapsulated it in an alginate/chitosan electrostatically cross-linked hydrogel as shown in Figure 11D^[152]. This hydrogel protects nanozyme from degradation in the gastrointestinal environment and achieves pH-responsive release in the weakly alkaline environment of the colon. This system reshapes the intestinal microecology through spectral antioxidation and specific antibacterial properties to alleviate colitis: W-PB nanozyme itself can efficiently eliminate excessive reactive oxygen and nitrogen species, reduce oxidative stress, and inhibit the STING pathway to weaken inflammation. The released tungsten ions can specifically inhibit the excessive proliferation of pathogenic Enterobacteriaceae by competitively replacing molybdenum cofactors. In the dextran sulfate sodium-induced colitis model, as shown in Figure 11E, oral W-PB hydrogel treatment demonstrated significant efficacy. Histological analysis [Figure 11F] further confirmed that H&E staining showed that the colonic mucosal structure in the W-PB gel group was intact and there was no obvious infiltration of immune cells. Alcian blue/Periodic acid-Schiff staining also indicated that its goblet cell structure and mucin secretion were effectively protected, verifying the advantages of this strategy in repairing the intestinal barrier and reshaping the microecology.

In addition to the basic antioxidant and microecological regulation functions, some nanozyme-hydrogel systems also have additional functions such as imaging, anti-fibrosis and reduction of parenteral complications, providing new ideas for the multi-dimensional treatment of IBD. For instance, Cao et al. achieved an integrated diagnosis and treatment of inflammation and anti-fibrosis guided by computed tomography imaging by using dextran-coated CeO₂ nanozyme^[153]. The ZnCe_γO₂/Se oral hydrogel designed by Kan et al. can achieve dual tissue protection by activating the Nrf2 antioxidant axis and inhibiting ferroptosis^[154].

Moreover, Wu et al. constructed inulin hydrogel that combines PB nanozyme with nattokinase^[155]. After oral administration, it can not only eliminate ROS and lyse intestinal microthrombi, but also alleviate extraintestinal complications related to ulcerative colitis (such as anxiety and depression phenotypes) by regulating the microbiota-gut-brain axis.

Others

Prolonged hyperglycemia can lead to organ failure and tissue damage, thereby triggering various complications. Therefore, accurate and timely monitoring of blood glucose levels is of paramount importance for the prevention and management of diabetes. With advances in clinical testing, home-based health monitoring, and personalized treatment, convenient glucose detection methods have attracted widespread attention^[156]. On one hand, glucose detection using blood-alternative samples such as sweat, interstitial fluid, tears, saliva, and urine has been extensively investigated; on the other hand, visual, continuous, and non-invasive glucose monitoring technologies are also continually advancing and being refined^[157-161].

Building upon these shared design principles, metal nanozyme-hydrogel systems have been extensively integrated into wearable biosensing platforms, where their catalytic responsiveness can be directly translated into measurable electrical or optical signals. Driven by these advances, wearable devices are becoming increasingly visible in healthcare^[162,163]. Yang et al. developed a wearable non-enzymatic electrochemical sensor for sweat glucose detection. The sensor is functionalized with a highly hydrophilic gel that rapidly concentrates sweat molecules on its surface. AuNPs subsequently oxidize glucose in the sweat to gluconolactone and H₂O₂, enabling real-time and non-invasive monitoring of glucose. Moreover, ZIF-8-C further catalyzes the oxidation of the generated H₂O₂ into hydroxyl radicals, thereby endowing the wearable glucose sensor with high antibacterial activity^[159]. In addition, colorimetric sensors have been developed as a convenient and intuitive technology for detecting various analytes. In a complementary study, Fei et al. designed and introduced a Fe₃O₄@MXene-Au nanocomposite with exceptional peroxidase-like activity for the first time in the field of nanozymes^[160]. Based on the enzyme-mimicking properties of this material, they developed a colorimetric biosensor for glucose detection, which exhibited high selectivity toward glucose and was successfully applied to the analysis of human blood samples with satisfactory recovery rates. Furthermore, a portable detection platform integrated with an agarose hydrogel and smartphone-based readout was constructed, demonstrating promising potential for on-site and visual monitoring of glucose.