The recent research progress in the application of the nanozyme-hydrogel composite system for drug delivery

Abstract

Hydrogels, comprising 3D hydrophilic polymer networks, have emerged as promising biomaterial candidates for emulating the structure of biological tissues and delivering drugs through topical administration with good biocompatibility. Nanozymes can catalyze endogenous biomolecules, thereby initiating or inhibiting in vivo biological processes. A nanozyme-hydrogel composite inherits the biological functions of hydrogels and nanozymes, where the nanozyme serves as the catalytic core and the hydrogel forms the structural scaffold. Moreover, the composite can concentrate nanozymes in targeted lesions and catalyze the binding of a specific group of substrates, resulting in pathological microenvironment remodeling and drug-penetrating barrier impairment. The composite also shields nanozymes to prevent burst release during catalytic production and reduce related toxicity. Currently, the application of these composites has been extended to antibacterial, anti-inflammatory, anticancer, and tissue repair applications. In this review, we elucidate the preparation methods for nanozyme-hydrogel composites, provide compelling evidence of their advantages in drug delivery and provide a comprehensive overview of their biological application.

1. Introduction

Over the past two decades, nanozymes have emerged as a rapidly expanding and diverse field of study from numerous global research groups, resulting in a substantial body of literature (Huang et al., 2019; Wu et al., 2019; Jiao et al., 2020; Li & Liu 2021). The definition of nanozymes has gradually evolved from immobilized catalysts or enzymes on nanomaterials to inorganic nanomaterials that exhibit surface catalytic properties (Zandieh & Liu, 2024). Notably, nanozymes exhibit favorable biocatalytic properties (Zhang et al., 2019). Like natural enzymes, the catalytic activity of nanozymes is affected by both intrinsic and external factors. Various intrinsic features, such as size and morphology, and external factors like pH and temperature, have been regarded as the main factors that affect the catalytic performance of nanozymes (Le et al., 2023). Nevertheless, nanoparticle-based nanozymes may undergo spontaneous accumulation during reactions, leading to a significant reduction in catalytic activity (Long et al., 2020). Some nanozymes are highly stable and difficult to excrete from the body, while others are easily metabolized and prone to inactivation in the living system. Furthermore, the potential toxic effects of excessive accumulation of certain nanozymes in the body necessitate careful evaluation of their biosafety when employed in drug delivery systems. Among the array of materials, hydrogels have been harnessed across various medical domains. The ability of these materials to emulate the microstructure of the extracellular matrix (ECM) arises from the presence of a three-dimensional hydrophilic network (Gaharwar et al., 2014), which endows them with high ductility (Basurto et al., 2022), substantial water content (Dimatteo et al., 2018), and proficient oxygen permeability (Su et al., 2021).

Skin impairment resulting from various factors such as injuries, infections, and diseases has become a pervasive global concern (Blanpain, 2010). Furthermore, emerging therapeutic modalities like Photodynamic Therapy (PDT) have progressively garnered attention within the realm of anti-tumor therapy. Numerous publications have substantiated the individual efficacy of both nanozymes and hydrogels in the realm of drug delivery (Alinaghi et al., 2013; Liu & García, 2016; Tang et al., 2021). However, considering the intricate microenvironment within organisms and the multifaceted pathogenesis of certain diseases, reliance on a single nanoparticle is insufficient (Yu et al., 2015; Zhang et al., 2022). Thus, nanozyme-hydrogel composites have garnered increased amounts of attention. Both components have extensive applications in the delivery of therapeutic agents for diverse diseases, and they have various functions. The composites possess not only the efficient catalytic performance inherent to nanozymes for reactive oxygen species (ROS) elimination but also integrate the stability and adhesive properties of hydrogels. The hydrogel component acts as a protective barrier facilitating the sustained release of nanozymes, while the nanozymes themselves contribute to the adherence of the hydrogel. This addresses challenges related to the tendency of nanozymes to precipitate and aggregate, as well as the issue of hydrogel adhesion deterioration. Consequently, this approach enables controlled spatiotemporal drug release and microenvironmental remodeling, thereby augmenting therapeutic efficacy (Du et al., 2017; Tu et al., 2022) (Table 1). In this review, we elucidate the preparation methods for nanozyme-hydrogel composites, provide compelling evidence of their advantages in drug delivery and provide a comprehensive overview of their biological application.

Table 1.

Pros and cons of nanozymes, hydrogels, and nanozyme-hydrogel composites for drug delivery.

Drug delivery system	Advantages	Disadvantages	Reference
Nanozyme	High enzyme activity, monomer structural stability, high substrate selectivity	Susceptible to clearance by the intrinsic immune system, prone to aggregation and precipitation in the solution, rapid attenuation in catalytic activity	(Jiao et al., 2019; Liu et al., 2021; Shen et al., 2022)
Hydrogel	Stability against erosion, muco-adhesion, and sustainable drug release, injectability in deep tissue	Weak muco-penetration, and delicate structure	(Mou et al., 2022)
Nanozyme-hydrogel Composite	Controllable spatio-temporal drug release, microenvironment remodeling, higher compatible with various drugs, and all advantages inherited from nanozymes and hydrogels	More complex preparation methods	(Jiao et al., 2019)

2. Literature search method

We conducted a systematic literature search to acquire the latest information relevant to the topic of our study. We searched PubMed. We employed a combination of keywords and subject headings to ensure comprehensive coverage of relevant literature. The search period ranged from 2013 to 2024, and the literature screening process involved preliminary screening of titles and abstracts, followed by full-text reading to identify literature meeting inclusion criteria. Additionally, we manually examined the reference lists of each included study to ensure no important research was overlooked.

Key search terms included but were not limited to:

(Nanozyme) and (Hydrogel) and (Drug delivery)

3. Preparation of nanozyme-hydrogel for drug delivery

A range of nanozymes exhibiting catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), oxidase (OXD) and glucose oxidase (GOx) activities were employed in conjunction with the hydrogel (Gu et al., 2024). Nanozymes can be incorporated into the hydrogel network by first mixing, followed by gelation to trap nanozymes within the hydrogel (Ning et al., 2022). The porosity of the hydrogel matrix can be directly modulated by changing the formulation of the nanozyme-hydrogel composites to achieve sustained release. A silk-based hydrogel incorporating CuTA nanozyme (a metal-organic framework (MOF) nanozyme amalgamating copper ions and tannic acid)—denoted as the CuTA@SF hydrogel—was engineered by Cao et al. While the integration of copper ions into the hydrogel enlarges the pores, the inclusion of tannic acid serves to constrict them, preserving the scaffold’s mechanical properties and ensuring the gradual release of nanozymes (Zhang et al., 2021). This phenomenon may be attributed to the higher concentration of tannic acid in the hydrogels, which contributes to increased crosslinking density through the formation of hydrogen bonds (Wang et al., 2023). Nanozyme-hydrogel composites can also be generated through self-assembly processes, and under these conditions, both components interact with each other via multiple mechanisms (Shen et al., 2022). In physically crosslinked composites, noncovalent interactions such as hydrogen bonding, hydrophobic interactions, electrostatic interactions, and π–π stacking interactions play crucial roles in strengthening the structural rigidity of the components, although these interactions are weak and labile (Zhao et al., 2020; Zhou et al., 2022). Zhou et al. fabricated composites via a Schiff base reaction, which rendered the composite self-healing when viscous supplementation was needed. Conversely, in chemically crosslinked composites, covalent bonds are forged between two components, thus providing greater mechanical strength. In addition to Schiff base bonding, chemical boron ester bond crosslinking can also achieve self-healing properties in composites (Li et al., 2022). In addition to the organization of nanozymes in hydrogels, nanozymes can also serve as shells for encapsulating hydrogel microspheres (Shen et al., 2022). Moreover, inorganic nanozymes can be cultivated in situ within the gel matrix by loading nanozyme precursors into the gel initially and subsequently reducing the precursors into nanoparticles (Huang et al., 2021). Jia et al. employ catechol-containing molecules as chelating agents to facilitate the formation of catechol − metal complexes. Subsequently, they harness these complexes as polymerization catalysts, enabling the self-catalyzed gelation of hydrogels at room or low temperatures, obviating the need for external stimuli (Figure 1).

Figure 1.

Three distinct nanozyme-hydrogel configurations. (A) Nanozymes covalently immobilized within a hydrogel matrix; (B) nanozymes non-covalently immobilized within a hydrogel matrix; (C) nanozyme-functionalized hydrogel microsphere (drawn by the authors).

In general, to better harness the activity of nanozymes, researchers have the following consensus on the chemical and physical structure of hydrogel (Nele et al., 2020):

1. Chemical stability: Chemical stability encompasses the intrinsic chemical stability of the nanozymes and the hydrogel, as well as the stability between them. The substrate of the nanozyme should not react with the hydrogel, and the binding of the hydrogel to the nanozyme should not occupy the active sites of the nanozyme. The chemical composition of hydrogels and nanozymes must ensure stability in a biological environment without causing adverse immune reactions.

2. Mechanical strength and elasticity: Hydrogels must possess sufficient mechanical strength to maintain their structure, while also having enough elasticity to adapt to dynamic biological environments. Nanozymes can dynamically regulate the redox balance within the hydrogel, providing it with long-term and repeatable adhesiveness. This balance is crucial for applications such as wound healing and tissue engineering.

3. Porosity: The porosity of hydrogels affects the loading and release rates of drugs. High swelling capacity ensures that hydrogels can absorb many biological fluids, which is critical for the sustained drug release and bioactivity of the embedded nanozymes.

4. Surface functionalization: To enhance the interaction between nanozymes and hydrogels, surface functionalization is commonly employed. This includes the introduction of functional groups that can covalently or non-covalently bind with nanozymes, thereby improving the stability and activity of the composite material.

5. Hydrophilic and hydrophobic: The hydrophilicity or hydrophobicity of drugs significantly influences their encapsulation within nanozyme-hydrogel systems and their subsequent release profiles. The properties of the nanozymes should be compatible with those of the hydrogel.

6. Compatibility of drugs: The drug should not chemically react with the composite and should be uniformly distributed within the hydrogel, allowing for stable and controlled release. Additionally, proper biocompatibility and nontoxicity should also be taken into consideration.

7. Time effect: The decomposition of the hydrogel should occur after the nanozymes, and drugs have taken effect. The hydrogel should not lose its activity even after multiple cycles of dissolution and solidification through photothermal effects. Additionally, the nanozymes will help the hydrogel maintain sustained adhesiveness (Table 2).

Table 2.

Pros and cons of covalently immobilized, non-covalently immobilized, and microsphere.

Combination mode	Advantages	Disadvantages	Reference
Nanozymes covalently immobilized within a hydrogel matrix	Highly stable immobilization, less enzyme leaching and long-lasting nanozyme activity	Complex preparation process, may require specific chemical modifications and immobilization might reduce nanozyme activity	(Nele et al., 2020; Li et al., 2022)
Nanozymes non-covalently immobilized within a hydrogel matrix	Relatively simple preparation, preserves original nanozyme activity and applicable to various hydrogels	Lower stability, nanozymes may leach over time and potential instability in biological environments	(Nele et al., 2020; Zhao et al. 2020; Zhou et al. 2022)
Nanozyme-functionalized hydrogel microsphere	Increased surface area enhances catalytic efficiency, facilitates targeted delivery within the body and effective controlled drug release	Complex preparation process, requires precise control of microsphere size and morphology and potential aggregation of microspheres affecting drug release	(Shen et al., 2022)

The inherent nature of nanozyme-hydrogel composites enables them to be highly compatible with various drugs. Drugs can be loaded into a composite system by directly embedding them in nanozymes or hydrogels. Drugs can be incorporated with nanozymes and subsequently introduced into a hydrogel solution through blending or encapsulation. The method of loading onto the nanozyme depends on the desired relationship between sustained drug release and nanozyme activity. Hydrophilic drugs are readily incorporated into hydrophilic hydrogel matrices due to their compatibility with the aqueous environment and the hydrogel’s network structure allows the drugs to be evenly distributed throughout the matrix via hydrogen bonding and electrostatic interactions (Dimatteo et al., 2018). Hydrophobic drugs tend to aggregate in aqueous environments and are less compatible with hydrophilic hydrogel matrices. To overcome this, hydrogels can be modified with hydrophobic domains or amphiphilic molecules that enhance the encapsulation efficiency of hydrophobic drugs. Li et al. achieved continuous drug release by associating nanozymes with doxorubicin (Zhou et al., 2022). In contrast, Ning et al. gelated a hydrogel by simply blending the drug with a nanozyme-hydrogel composite solution, wherein the nanozyme served as a switch, releasing the drug in response to stimulation by a melting hydrogel (Liu et al., 2021).

4. Drug release from nanozyme-hydrogel composites

Nanozyme-hydrogel composites encapsulate nanosized drugs within three-dimensional polymer matrices, facilitating improved local drug delivery. Various hydrogel formulations have been developed to precisely target drugs to specific disease sites, such as the spinal cord (Chvatal et al., 2008; Baumann et al., 2010), the eye (Kapoor & Chauhan, 2008; Jung et al., 2013), and the skin. These formulations enable controlled spatiotemporal drug release, minimizing side effects on normal tissues.

Injectable hydrogels facilitate precise and targeted drug delivery. Nanozyme-hydrogel composites can exist in a sol state at room temperature and can undergo conversion into a solid gel state in situ upon encountering the physiological environment in vivo (He et al., 2022). Li et al. leveraged enzymatic activity to induce rapid gelation of hydrogels postinjection (Li et al., 2022). Dynamic imine bonds and dynamic acylhydrazone bonds, as established by Zhao et al., mediate the connection between nanozymes and hydrogels (Zhao et al., 2022). In the initial stages, the strength of the hydrogel decreased due to incomplete crosslinking of the dynamic bonds. This characteristic endows the hydrogel with the distinct advantage of noninvasive injection.

The encapsulated drugs include hydrophilic drugs and hydrophobic drugs. Hydrophilic drugs are typically released rapidly from hydrophilic gels due to the high affinity of the drug for the aqueous phase. This rapid release can be advantageous for applications requiring immediate therapeutic effects but may necessitate modifications for sustained release. Although the release of hydrophobic drugs from hydrogels is generally slower compared to hydrophilic drugs due to their lower solubility in the aqueous phase. This slower release is beneficial for prolonged therapeutic effects. However, ensuring a consistent release rate requires careful optimization of the hydrogel composition and structure.

4.1. Site-specific drug release

The site-specific delivery of drugs, particularly anticancer drugs, is essential for enhancing the therapeutic efficacy of drugs in targeted organs and mitigating side effects in other normal organs. The nanozyme-hydrogel composites gelated after being injected in vivo. Afterward, they concentrate encapsulated drugs onto the tissue to which they adhere and therefore achieve site-specific drug release.

The adhesive characteristics of the composites draw inspiration from mussels, which are renowned for their robust adhesion in seawater due to the presence of 3,4-dihydroxyphenylalanine (DOPA)-containing mussel foot proteins. The catechol side chain of DOPA engages with various substrate surfaces through diverse noncovalent interactions and chemical crosslinking. In addition to catechol-based adhesive hydrogels, polyphenol-based hydrogels such as tannic acid (TA)-based hydrogels also exhibit strong adhesiveness (Shao et al., 2018; Shin et al., 2019). However, the adhesiveness of the hydrogel gradually decreases as it oxidizes. Long-term adhesiveness enhancement is essential for site-specific drug release and can be achieved by incorporating nanozymes into hydrogels. Jia et al. utilized natural polyphenol tannic acid (TA)-functionalized ultrasmall Ag nanoparticles (Ag NPs) to modulate the dynamic redox equilibrium of phenol-quinone, which provided sufficient polyphenolic hydroxyl groups inside the hydrogel and endowed the nanozyme-catalyzed hydrogel with long-term and repeatable adhesiveness, conferring long-lasting and repeatable adhesiveness to the adhesive hydrogel (Jia et al., 2021).

Site-specific drug delivery via nanozyme-hydrogel composites can be more precise to subcellular organelles. Zhang et al. employed a mitochondrion-targeted nanozyme-hydrogel composite system to treat ischemia‒reperfusion (IR) injury (Zhang et al., 2021). Mito-Fenozymes are composed of triphenyl phosphonium (TPP) as a surface-functionalized ligand, recombinant human ferritin nanocage (FTn) (Wang et al., 2023) as the protein scaffold and MnO₂ as the catalytic core. TPP directs the whole system to target mitochondria and thus bypass lysosomes. A biomimetic tissue adhesive hydrogel (Mitofegel) was utilized to load Mitofenozymes. Compared with intravenous injection of free Mitofozymes, local release of Mitofenozyme via transplanted Mitofegel-based cardiac patches not only was more sustainable but also resulted in a 10% greater concentration of Mitofozymes in the mitochondria.

4.2. Controlled drug release

Controlled burst release offers advantages in maintaining released drugs within their therapeutic window, especially given the often-nonlinear pharmacokinetic profile of therapeutic drugs. Qiu et al. pioneered the concept of photothermal activable black phosphorus (BP) nanozyme-hydrogel composites (Jia et al., 2021). In their study, black phosphorus (BP) was incorporated into agarose to form a composite. BP acted as a photothermal transducing agent (PTA) capable of converting light into thermal energy, thereby elevating the temperature of the hydrogel matrix. Consequently, the agarose hydrogel underwent reversible hydrolysis and softening, allowing rapid diffusion of the drug from the matrix into the surrounding environment. However, prolonged or intense light exposure might lead to the generation of ROS, which could potentially damage the hydrogel matrix and the nanozymes themselves. Elevated temperatures can enhance the release rate but may also impact the stability and activity of nanozymes. For instance, CeO₂ nanozymes exhibit phosphatase-like activity that is sensitive to temperature changes (Gai et al., 2023). High temperatures might enhance the initial reaction rate, but prolonged exposure can lead to thermal deactivation of the nanozymes. This necessitates careful control of light intensity and duration to balance drug release and nanozyme activity. Furthermore, the hydrogel underwent further hydrolysis and melting under intensified laser power, after which the products were ultimately degraded into oligomers and subsequently excreted through the urine. Building upon this, Li et al. devised a composite for delivering doxorubicin (DOX) via the use of polydopamine (PDA) and Fe (III) ions and a sodium alginate-grafted-dopamine hydrogel carrier. This system responds to near-infrared (NIR) and pH changes, enabling more precise and intelligent delivery of drugs to melanomas (Zhou et al., 2022). Activable multimodal nanozyme-hydrogel composites release their loaded drugs under sonic or photothermal stimulation. In this case, NIR irradiation and sonication induce melting of the hydrogel, accelerating the release of sonosensitizers and nanozymes into targeted lesions (Zhang et al., 2021). While sonication is effective in breaking the hydrogel network, it can also generate heat and cause physical damage to the nanozymes. Other studies have indicated the possibility of controlled drug release via magnetic-hyperthermia transition. For instance, Wu et al. utilized Fe₃O₄ nanozymes, PEGylated nanoparticles, and α-cyclodextrin (α-CD) to prepare a magnetic hydrogel nanozyme (MHZ), which could undergo disruption after receiving magnetic hyperthermia stimulation and subsequently release nanozymes (Wang et al., 2023). The application of a magnetic field can improve the targeted delivery and release of drugs. However, the magnetic field strength and duration need to be optimized to avoid potential overheating of the nanozymes, which could negatively impact their catalytic activity.

5. Applications of nanozyme-hydrogel composites

In recent years, various drug delivery systems, including hydrogels, have been designed and developed, offering safer and more effective approaches for cancer treatment (Cheng et al., 2022; Gai et al., 2023). However, the efficacy of these systems is impeded by a series of in vivo biological barriers, encompassing blood circulation, vascular extravasation, accumulation at the tumor site, depth of stromal infiltration, and internalization by tumor cells, which collectively limit intracellular drug release. Furthermore, conventional drug delivery systems are susceptible to challenges such as low drug loading capacity, intricate synthesis procedures, premature drug leakage or delayed release, and potential long-term toxicity stemming from the prolonged presence of carriers within the body (Xu et al., 2022; Li et al., 2023).

Although in theory, the controlled release of drugs by nanozyme hydrogel composite is possible, the long-term effects of nanozyme hydrogel composites in the body remain incompletely understood, demanding extensive research into potential chronic implications including its accumulation and biodegradation (Table 3).

Table 3.

Applications of nanozyme-hydrogel composites.

Drug	Tested models (cell line(s)/animals)	Components of nanozyme-hydrogel	Mechanism	Performance	Ref.
CeO2	C57BL/6 rats	CCNZ1:Alg1.5 Composites	ROS Depleting	After three doses, the weight was 5% higher than that of 5-aminosalicylic acid treated mice.	(Cheng et al., 2022)
AIPH	4T1 cells/BALB/c mice	FeS2 + Agarose hydrogel	PTT + free radical therapy + GSH Depletion	Tumor volume of the experimental group was 1/9 of the control group	(Ning et al., 2022)
CpGODN	CT26 cells/BALB/c mice	DA-CQD@Pd SAN + APS	Immunotherapy + ROS depleting	Tumor growth was completely inhibited and the percentages of CD4+ and CD8+ T cells in tumors were the highest among all the groups	(He et al., 2022)
Doxorubicin	B16F10 cells/BALB/C nude mice	PFD + SD	Chemotherapy + PTT	Tumor tissue in the experimental group was almost 0, while in the control group, it was 800 mm3	(Li et al., 2023)
LDO	4T1 cells/BALB/c mice	CoMnFe-LDO+ gelatin-hydroxyphenyl	ST+PTT+CDT	Tumor mass of the experimental group was about 1/7 of the control group	(Xu et al., 2022)
MSC	Sprague-Dawley (SD) rats	Ceria nanozyme + Chitosan	Autophagy of MSCs + ROS depleting	Effective hindlimb step ratio of rats in the experimental group is 6.2-fold higher than that of the controlled group	(Xu et al., 2023)
N/A	Diabetic rats	ODex/gC/ MoS2@Au@BSA hydrogel	ROS depleting O2 and supply	Wound healing in the experimental group was about 90%, compared with almost no change in the control group	(Li et al., 2022)
CS	SW135/BL6J/C57 mice	Mn3O4@CS	ROS depleting	Thickness and completeness of the cartilage surface were maintained after injection	(Wang et al., 2023)
Ce6	4T1 cells/BALB/c mice	PB + Agarose Hydrogel	PTT + SDT + O2 supply	Tumor inhibition rate was 90% compared with the control group and 80% compared with the PB group	(Wang et al., 2022)
miRNA	Sprague–Dawley (SD) rats	PCN-miR/Col + Agarose hydrogel	Reshape the oxidative wound microenvironment and deliver proangiogenic miRNA	Wounds in the experimental group were about half the size of those in the control group.	(Wu et al., 2019)
H2O2	MRSA/AREC/Kunming mice	FePO4 − HG	ROS depleting	Bactericidal rate was 98.21% toward MRSA and 96.12% toward AREC	(Liao et al., 2022)
N/A	HGF/ SD Rats	PDMO hydrogel	ROS Depleting + antibacterial	Antibacterial rates of PDMO hydrogel were nearly 100%	(Hu et al., 2023)
Cu2Se	Cal-27/ BALB/c mice	Cu2Se + SNP + ALG hydrogel	PTT + GT	Oral squamous cell carcinoma has been virtually eliminated	(Zhong et al., 2024)
ZIF-8	SD rats	ALG-ZIF-8	ROS depleting	Enhancing cardiac function, mitigating remodeling, and boosting angiogenesis	(Zhong et al., 2024)

Abbreviations: SDT: sonodynamic therapy; PTT: photothermal therapy; PB: Prussian Blue; Ce6 = Chlorin e6; AIPH: a typical free radical initiator; NIR: near-infrared; GSH: glutathione; PCN-miR: Ceria nanozyme + miRNA + PEI25K; PFD: polydopamine-Fe (III)-doxorubicin nanoparticles; SD: sodium alginate-graft-dopamine; MSC: mesenchymal stem cell; APS: ammonium persulfate; 4T1 cells: mouse breast cancer cell line; CT26 cells: mouse colorectal cancer cells; B16F10 cells: mouse melanoma cell line; miRNA: microRNA; ROS: reactive oxygen species; CCNZ: chitosan-coated CeO₂ nanozyme; Alg: alginate; MRSA: methicillin resistant Staphylococcus aureus; AREC: ampicillin resistant Escherichia coli; BSA: bovine serum albumin; ODex: oxidized dextran (ODex), gC: glycol chitosan; MoS₂: molybdenum disulfide; Au: gold; LDO: layered double oxides; CS: chondroitin sulfate; SW135: human chondrocyte cell line; Mn₃O₄: trimanganese tetroxide; PDMO hydrogel: polyvinyl alcohol (PVA), 3,4-dihydroxy-Dphenylalanine (DOPA), and MnO₂ nanozyme; HGF: human gingival fibroblasts; GT: gas therapy; SNP: sodium nitroprusside dihydrate; ZIF-8: zeolite imidazole framework-8.

5.1. Nanozyme-hydrogel composites for anticancer therapy

Malignant tumors represent a significant threat to human health (Sanson et al., 2021). Currently, clinical interventions for malignant tumors encounter limitations, including insufficient efficacy and specificity and the emergence of severe side effects (Harbeck & Gnant, 2017; Wang et al., 2020). The tumor microenvironment (TME) features weak acidity, a reducing environment, high levels of reactive oxygen species, hypoxia, overexpressed enzymes, and high levels of adenosine triphosphate (Peng et al., 2022). By leveraging the acidic pH and elevated concentrations of hydrogen peroxide (H2O2) within the TME, nanomedicines can initiate specific catalytic reactions, enabling the realization of tumor catalytic therapy (Li et al., 2018; Mallakpour et al., 2020). Nanozyme-hydrogel composites can respond to these characteristic factors of the TME to achieve site-specific drug release or enhance the anticancer activity of drugs. The incorporation of stimuli-responsive NPs or nanozymes into hydrogels results in stimuli-responsive composites. By harnessing photosensitivity, thermal sensitivity, and in situ injectability, nanozyme-hydrogel composites can transition from a sol state at room temperature to a solid gel state in situ upon exposure to the physiological environment in vivo (Figure 2). In response to stimulation, the hydrogel melts to release nanozymes as well as therapeutic agents. The level of ROS in the TME can be modulated through the catalytic activity of nanozymes, enabling the therapeutic agent to achieve the desired effect.

Figure 2.

Stimuli-responsive nanozyme-hydrogel composites for anticancer therapy. The nanozyme and hydrogel composite is injected into the breast tumor site with precise localization. Dual stimulation, involving ultrasound (US) and near-infrared (NIR) light, activates the nanozyme, generating heat that dis­solves the hydrogel and facilitates the controlled release of drugs and nanozyme. This combination of Sonodynamic Therapy (SDT), Photodynamic Therapy (PDT), and other treat­ments surpasses the efficacy of individual therapies, aiming to effectively eradicate tumor cells (Drawn by the authors).

When exposed to near-infrared (NIR) laser irradiation, the nanozyme efficiently converts light energy into heat energy, inducing hyperthermia and elevating the temperature of the hydrogel. Subsequently, the hydrogel undergoes reversible hydrolysis and softening. This hydrolysis process leads to the controlled release of nanozymes and therapeutic agents. Elevated temperature also promotes increased blood flow within local tumor tissue, addressing radiological resistance. Along with therapeutic agents, nanozymes disperse into the tumor microenvironment, rapidly breaking down endogenous H₂O₂. This process generates a substantial amount of oxygen, mitigating issues associated with tumor hypoxia. Consequently, this approach enhances the efficiency of photothermal therapy (PTT), the tumor hypoxia micro­environment, and sensitivity to radiotherapy (RT). The nanozyme-hydrogel system, administered through intratumoral injection, not only facilitates improved PTT-RT outcomes but also serves as a controller for storing and releasing nanozymes. This feature enables a single injection to support multiple treatments in vivo.

Wu et al. introduced a magnetic hydrogel nanozyme (MHZ) by merging Fe₃O₄ nanoparticles with PEGylated counterparts and α-cyclodextrin (Wu et al., 2019). In this composite, diverse components are meticulously engineered to enhance the dispersion of •OH in tumor tissue. Primarily, the shear-thinning characteristics of the hydrogel enable the facile injection of MHZ into the tumor site through a needle. Furthermore, the dynamic transition between sol-gel states exhibited by the hydrogels upon heating significantly augments the contact area between the nanozymes and the tumor site. Additionally, the D-mannitol-enriched hydrogel promoted the diffusion of nanoparticles into the tumor tissue by inducing cell shrinkage through dehydration. In the acidic TME, the Fe₃O₄ nanozyme displays peroxidase-mimicking activity and can generate hydroxyl radicals (•OH) through the Fenton reaction. A noninvasive external alternating current magnetic field (ACMF) heats magnetic media via Néel Relaxation/Brownian Relaxation-like mechanisms, subsequently rapidly increasing the tumor temperature (42 °C) and increasing •OH production to induce tumor cell apoptosis. The injectable MHZ inside the breast tumor amplifies •OH production and exacerbates oxidative damage to tumor cells. An increase in •OH consequently disrupts the expression of defensive heat shock protein 70 to impede tumor cell defense against hyperthermia. MHZ can be used to synergistically combat tumors via hyperthermia therapy and catalytic therapy and inhibits tumor growth fivefold more strongly than in the control group and threefold more strongly than in the nanozyme-treated group without severe side effects on normal tissues.

Zhu et al. recently employed an antitumor agarose hydrogel for the delivery of aggregation-induced emission luminogen (AIEgen). Prussian blue (PB) nanozymes serve as photothermal protagonists to promote hydrogel disintegration and activate catalase (CAT) to exhaust H₂O₂. Under low-power white light irradiation, AIEgens convert oxygen into reactive oxygen species (ROS) to ablate tumors. Importantly, this hydrogel could persist in tumors for at least 48 h in vivo after injection and underwent multiple rounds of treatment after a single injection (Zhu et al., 2021). Wu et al. developed a hybrid enzyme-silk fibroin (SFG) hydrogel system composed of Pt-decorated hollow Ag − Au trimetallic nanocages (HGN@Pt) and glucose oxidase (GOx). The hydrogel allows repeated photothermal treatments without additional injections. Even though the system was in a hypoxic environment, it could synergistically activate a cascade reaction, which guaranteed the O₂ supply, led to glucose consumption, and even eradicated breast tumors (Wu et al., 2021).

The range of use of nanozyme-hydrogel composites has also been expanded to include photothermal immunotherapy. He et al. introduced a composite tailored for immunotherapeutic applications (He et al., 2022). In this study, a phenolic single-atom nanozyme (SAN) was synthesized through the in-situ formation of a single Pd atom on catechol-grafted carbon-quantum-dot (DA-CQD@Pd) templates. Subsequently, a bioadhesive injectable hydrogel consisting of DACQD@Pd SAN and the immune adjuvant CpGODN materialized through SAN-catalyzed free-radical polymerization. This hydrogel strongly adhered to tissues and could act as a local hub, orchestrating the sustained release of the immune adjuvant CpGODN to potentiate the antitumor immune response. The coadministration of the composite and the checkpoint inhibitor anti-PD-L1 completely inhibited colorectal tumor growth only four days after a single therapy. Furthermore, the composite triggers adaptive antitumor immune responses, preventing tumor recurrence and metastasis.

Nanozyme-hydrogel composites can also serve as a platform for sonodynamic therapy (SDT). Zhu et al. developed a polyfunctional hydrogel (PB+Ce6@Hy) to codeliver the nanozyme PB and the sound-responsive agent chlorin e6 (Ce6) to achieve both PTT and SDT (Wang et al., 2022). Following local injection into tumor tissue, the hydrogel responded to an 808 nm laser and was heated and softened, thereby facilitating the release of PB and Ce6. PB interacts with endogenous H₂O₂ in situ, generating ample oxygen to amplify the Ce6-mediated SDT effect. After receiving PB+Ce6@Hy treatment, the average breast tumor weight was only 0.12 g, reflecting a 90% inhibition rate.

At present, the focus of tumor therapy has transitioned from monotherapy to combination therapy aimed at enhancing overall therapeutic efficacy. In addition to integrating the aforementioned strategies of sonodynamic therapy (ST) and photothermal therapy (PTT), Xu et al. augmented the nanozyme hydrogel platform with chemodynamic therapy (CDT) (Xu et al., 2022). Nanozymes proficiently convert endogenous H₂O₂ within the tumor microenvironment (TME) into highly specific reactive oxygen species (ROS), thus serving as therapeutic agents for CDT (Li et al., 2020; Mei et al., 2020). However, the efficacy of CDT is constrained by suboptimal H₂O₂ levels (∼100 μM) and weakly acidic conditions (∼pH 6.5) in the TME (Wang et al., 2017; Ye et al., 2022). Introducing a catalyst to facilitate TME remodeling, ensuring a sustained H₂O₂ supply and lowering the pH has emerged as a promising strategy for tumor therapy. GOx-mediated starvation therapy (ST) orchestrates the conversion of glucose and O₂ into gluconic acid and H₂O₂ (Wang et al., 2020; Yang et al., 2022), generating H₂O₂ within the confined confines of the TME while concurrently lowering the pH through gluconic acid production, thereby potentiating the CDT effect (Wang et al., 2010; Yue et al., 2015; Wang et al., 2020). Additionally, GOx induces a state of energy deprivation in tumor cells by impeding glucose metabolism. However, GOx activity is inhibited within the hypoxic TME. Selective nanozymes can consume H₂O₂ to generate O₂ under acidic conditions. Ye et al. synthesized a CoMnFe-LDO hydrogel composite employing layered double hydroxides (LDH) subjected to calcination with Co, Mn, and Fe, resulting in the formation of mixed metal oxides referred to as layered double oxides (LDO) (Ye et al., 2022). These agents were then incorporated into a gelatin hydrogel containing GOx, the hydrogel is transformed in a melt-gel process, releasing nanoenzymes that continue to kill tumor cells, culminating in the creation of a synergistic CDT/ST/PTT system for treating breast tumors. Consequently, after 11 days of treatment, the tumor mass in the experimental group was approximately 1/7th that of the control group, and the tumor volume was significantly controlled, while the weight of the mice did not ­significantly change.

Nanozyme-infused hydrogel formulations with chemotherapeutic payloads have potential for optimizing drug permeation and retention. Simultaneously, the increase in the localized temperature during PTT enhances cell membrane permeability and drug cytotoxicity, achieving a synergistic therapeutic outcome of ‘1 + 1 > 2’ (Zhang et al., 2022; Singh & Pal, 2023). Evolving from this synergy, a groundbreaking NIR and pH-responsive injectable nanocomposite hydrogel was pioneered by Li et al. This sophisticated hydrogel, which integrates sodium alginate-graft-dopamine (SD) and biomimetic polydopamine-Fe(III)-doxorubicin nanoparticles (PFD NPs), the hydrogel shows superior adhesion and drug permeability and is meticulously designed for the treatment of melanoma and the promotion of skin regeneration (Li et al., 2023). The composite effectively restrained tumor cell proliferation and migration through the orchestrated interplay of PTT, chemotherapy, and nanozymes. After a fortnight of treatment, the tumor tissue in the experimental group was virtually nonexistent, a stark deviation from that in the control group’s voluminous 800 mm³. Furthermore, the composite accelerated epidermal regeneration by annihilating bacteria, scavenging reactive oxygen species (ROS), and stimulating cell proliferation and migration.

Regardless of the mechanism of action of the loaded therapeutic agent, the function of the nanozyme in improving the tumor microenvironment, involving GSH depletion or ROS modulation, among other processes, has not been fully elucidated. While this may not seem directly related to drug delivery, it indeed is. Phan et al. suggested that the use of ROS-modulating nanozymes to enhance cancer immunotherapy is based on two mechanisms within the responsive TME: (1) modulation of tumor physiological parameters, including pH, oxygen levels, and immunosuppressive cells, to reprogram the immunosuppressive TME into a tumor-inhibiting, antitumor TME (Gabitass et al., 2011; Alizadeh et al., 2014; Solito et al., 2014); and (2) induction of immunogenic cell death (ICD) in tumor cells, subsequently releasing tumor-associated antigens (TAAs) that can be captured, processed, and presented by antigen-presenting cells (APCs), such as dendritic cells (DCs), priming naïve CD8+ and CD4+ T cells (Meng et al., 2021; Wang et al., 2021).

Despite numerous cell and animal experiments demonstrating the potential of nanozyme hydrogel composites in anti-tumor applications, their efficacy must be validated through human trials to exert a direct impact on tumor treatment.

5.2. The application of nanozyme-hydrogel composites in wound healing

In the context of wound healing and tissue repair, hydrogels are utilized primarily as dressings. However, the specific conditions at the wound site, such as hyperglycemia, excessive oxidative stress, hypoxia, and bacterial infection, may limit the therapeutic potential of hydrogels. In such situations, the incorporation of nanozymes becomes crucial for overcoming the body’s resistance to drugs or antibiotics supported by hydrogels. Chronic nonhealing wounds associated with diabetes or acute wound infections are particularly suitable for this combined approach. The healing process of a wound can be broadly divided into four stages: hemostasis, inflam­mation, proliferation, and remodeling. Therefore, scavenging free radicals and controlling the direction of macrophage polarization are crucial for promoting wound healing (He et al., 2024).

Wu et al. introduced an innovative ‘seed-and-soil’ strategy to address this challenge. This strategy transforms the oxidative wound microenvironment into a pro-regenerative state (the ‘soil’) and introduces proangiogenic miRNA cues (the ‘seed’) through the application of a miRNA-impregnated, redox-modulatory ceria nanozyme-reinforced self-protecting hydrogel (PCN-miR/Col) (Wu et al., 2019). PCN-miR/Col not only reshapes the initially hostile oxidative wound microenvironment but also preserves the structural integrity of the encapsulated proangiogenic miRNA within this oxidative milieu. After 10 days, the diabetic wounds treated with PCN-miR/Col exhibited markedly accelerated wound closure, with wounds in the experimental group reaching approximately half the size of those in the control group. Furthermore, the quality of the healed wounds improved, as characterized by highly organized collagen fiber alignment, skin appendage morphogenesis, functional new blood vessel formation, and enhanced oxygen saturation. Additionally, Yuan et al. developed a heparin-based hydrogel incorporating ultrasmall Cu_5.4O nanozymes. This composite effectively curtails the migration of macrophages and neutrophils through chemisorption within the hydrogel. Moreover, oxidative stress is alleviated by removing reactive oxygen species (ROS) from wounds, and angiogenesis is promoted by controlling the pore size of the hydrogel to achieve continuous Cu_5.4O release, resulting in substantial progress in wound healing (Wang et al., 2021).

Wu et al. conducted wound healing experiments focusing on restructuring blood vessels, while Zhang et al. aimed at reducing blood glucose levels around the wound to reshape the microenvironment. Zhang et al. integrated Au-Pt (gold-platinum) alloy nanozymes into a hydrogel (OHC) through a Schiff-base reaction between oxidized hyaluronic acid (OHA) and carboxymethyl chitosan (CMCS). This integration endowed the OHC hydrogel dressing with the ability to lower blood glucose, mitigate oxidative damage, and provide oxygen, emulating the functions of ­glucose oxidase and catalase. The combined effect of the OHC hydrogel and Au-Pt alloy nanoparticles (OHCNs) significantly improved the pathological microenvironment, thereby accelerating the healing of diabetic wounds (Zhang et al., 2022).

Li et al. integrated the aforementioned attributes (Li et al., 2022). Gold nanoparticles (Au NPs) can mimic natural Gox (Hu et al., 2020; Luo et al., 2020). However, uniform ultrasmall particles, which enhance activity, and modifiable functional groups on the surface of Au-NPs are lacking. Molybdenum disulfide nanosheets (MoS2 NSs) exhibit peroxidase (POD)-like activities under acidic conditions and superoxide dismutase (SOD)-like and catalase (CAT)-like activities under neutral conditions (Li et al., 2022). These properties mitigate oxidative stress and hypoxia at diabetic wound sites (Sang et al., 2019; Ren et al., 2020). Moreover, the abundant supply of oxygen fosters angiogenesis, collagen deposition, cell proliferation, and migration and expedites wound repair. Bovine serum albumin (BSA) decoration, in conjunction with the chemical composition of MoS₂ and Au NPs, reduces the particle size of Au, thereby enhancing GOx-like activity. The MoS₂@Au@BSA nanozyme, anchored within an injectable hydrogel crosslinked through a Schiff base network containing oxidized dextran (ODex), MoS₂@Au@BSA NSs, and glycol chitosan (gC), exhibited self-healing, shape adaptability, and tissue adhesion properties; facilitated diabetic wound healing by glucose consumption, bacterial eradication, ROS scavenging, and oxygen provision; and promoted epithelialization, collagen deposition, and angiogenesis.

In addition to the aforementioned applications, the composite material may also serve as a dressing for infected wounds, leveraging the inherent antibacterial properties of both the hydrogels and nanozymes. Zhu et al. developed a multifunctional hydrogel with multienzyme-like activity composed of mussel-inspired carbon dot reduced Ag (CDs/AgNPs) and Cu/Fe-nitrogen-doped carbon (Cu, Fe-NC). Due to the loss of glutathione (GSH) and the oxidase (OXD)-like activity of the nanozyme, which leads to the decomposition of O₂ into a superoxide anion radical (O^2-) and hydroxyl radical production (•OH), the multifunctional hydrogel demonstrated excellent antibacterial performance. The composite can serve as an anti-inflammatory bactericide by leveraging the catalytic activity of nanozymes to modulate the oxygen supply to infected wounds, thereby creating an environment unfavorable for bacterial growth. Liao et al. engineered an iron phosphate nanozyme − hydrogel (FePO₄−HG) that exhibited a positive charge and macroporous traits (Luo et al., 2009). FePO₄, which functions as a nanozyme with trienzyme-like activity, exhibits bactericidal effects via peroxidase-like catalytic activity within acidic infectious environments. Simultaneously, it offers protection to normal cells through synergistic anti­oxidant effects reminiscent of superoxide dismutase and catalase within neutral or weakly alkaline normal tissues. Examination of the results indicated that the bactericidal effect of the FePO₄−HG + H₂O₂ composite reached 98.21% against methicillin-resistant Staphylococcus aureus (MRSA) and 96.12% against ampicillin-resistant Escherichia coli (AREC), demonstrating low cytotoxicity.

The safety profile of nanozyme hydrogel composite systems in the human body requires further investigation, and the potential for unforeseen effects on human health remains unverified.

5.3. The application of nanozyme-hydrogel composites in other diseases

This complex can also be used to treat spinal cord injury (SCI). Mesenchymal stem cell (MSC)-based therapy has emerged as a promising strategy for the treatment of SCI, but its use is limited by the microenvironment. Xu et al. reported on a ceria nanozyme-integrated thermoresponsive in situ forming hydrogel (CeNZ-gel) that can enable dual enhancement of MSC viability and paracrine effects, leading to highly efficient spinal cord repair (Xu et al., 2023). The composites achieved 6.2 times the efficacy of the blank control.

Cheng et al. reported the development of a CeO₂-encapsulated chitosan (Cs) and alginate (Alg) hydrogel (CCNZ&Alg) for the treatment of ulcerative colitis (UC). This complex not only targets the inflamed colon and reduces the inflammatory response but also promotes mucosal healing (Wang et al., 2023). Furthermore, the composites can alleviate UC better than the clinical medication 5-aminosalicylic acid can by even a single-dose treatment. Similarly (Yang et al., 2023), Yang et al. synthesized a manganese oxide (Mn₃O₄) nanozyme with multienzyme activity, followed by physical loading into a thermosensitive hydrogel composed of poly(d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide)-based triblock copolymer (PDLLA-PEG-PDLLA). Due to the pronounced gelation behavior of Mn₃O₄ nanozyme-loaded PDLLA-PEG-PDLLA (MLPPP) at body temperature, the MLPPP nanozyme effectively targeted the inflamed colon following colorectal administration. With the establishment of a physical protection barrier and the sustained release of manganese oxide nanozymes, which exhibit diverse enzymatic activities and proficiently scavenge reactive oxygen species (ROS), the administration of the MLPPP nanozyme demonstrated high efficacy in treating mice with colitis.

Osteoarthritis (OA) is a chronic degenerative cartilage disease that involves oxidative stress-induced metabolic imbalance in chondrocytes and plays a crucial role in its occurrence and development (Gao et al., 2020; Zeng et al., 2021). Zhou et al. fabricated a MnO₂ nanozyme-encapsulated hydrogel by dispersing BSA-MnO₂ (BM) NPs into a hydroxyapatite (HA)/platelet-rich plasma (PRP) gel network crosslinked via a Schiff base reaction (Gu et al., 2024). Capitalizing on the self-healing and pH-responsive properties conferred by Schiff base bonds, the hydrogel not only served as a viscosupplement but also demonstrated pH-responsive release of BM NPs and growth factors present in PRP. The BM NPs exhibited the capacity to alleviate severe oxidative stress, while PRP promoted chondrocyte proliferation. In a rat OA model, the HA/PRP/BM hydrogel notably mitigated cartilage matrix degradation. Additionally, Wang et al. devised a cross-linked chondroitin sulfate (CS) hydrogel as a substrate for trimanganese tetroxide (Mn₃O₄) nanozymes for the treatment of OA in a mouse model (Wang et al., 2023). The Mn₃O₄ nanozyme, which possesses superoxide dismutase (SOD)-like and catalase (CAT)-like activities, mitigates oxidative stress-induced damage in cartilage. When combined with CS, the Mn₃O₄ nanozyme effectively protects cartilage.

Periodontitis is a chronic inflammatory disease originating from dental plaque characterized by the excessive accu­mulation of reactive oxygen species (ROS) (Hirschfeld et al., 2017), matrix metalloproteinases (MMPs), and other substances, leading to the destruction of periodontal ­tissues. Current primary therapeutic approaches, such as local me­chanical debridement and antibiotic delivery (H.R. et al., 2019), face challenges in effectively addressing intractable bacterial biofilms, mitigating excessive inflammatory responses, and regenerating impaired periodontal tissues (Slots, 2017; Liu et al., 2021). In this context, Xu et al. introduced the TM/BHT/CuTA hydrogel system, which was formed through the self-assembly of copper-based nanozymes (copper tannic acid coordination nanosheets, CuTA NSs) with the triglycerol monostearate/2,6-di-tert-butyl-4-methylphenol (TM/BHT) hydrogel. The negatively charged TM/BHT/CuTA can be retained at inflammation sites with a positive charge through electrostatic ­adsorption and subsequently hydrolyze in response to the increasing MMP associated with periodontitis, enabling on-demand release of the CuTA nanozyme. The released CuTA nanozyme exhibited antibacterial and antiplatelet properties. Additionally, as a metal-phenolic nanozyme, it can scavenge multiple ROS by mimicking the cascade process of superoxide dismutase (SOD) and catalase (CAT). Moreover, the CuTA nanozyme modulates macrophage polarization from the M1 to M2 phenotype through the Nrf2/NF-κB pathway, sequentially reducing proinflammatory cytokines, elevating anti-inflammatory cytokines, and enhancing the expression of osteogenetic genes. This alleviates inflammation and expedites tissue regeneration in periodontitis. Overall, this multifunctional nanozyme on-demand release platform (TM/BHT/CuTA) offers a promising strategy for periodontitis treatment (Hu et al., 2023; Xu et al., 2023). In a separate study, Hu et al. developed a composite, named the PDMO hydrogel, by incorporating polyvinyl alcohol (PVA), 3,4-dihydroxy-d-phenylalanine (DOPA), and MnO₂ nanozymes. The composite demonstrated the ability to scavenge various free radicals, including total ROS such as O₂^•- and •OH, thereby alleviating hypoxia in the inflammatory microenvironment. This is achieved by scavenging excess ROS and generating O₂ due to its SOD/CAT-like activity. Both composites improve the oral mucosal microenvironment through the use of nanozymes with SOD and CAT activities, ultimately achieving bactericidal and anti-inflammatory effects (Figure 3).

Figure 3.

The usage of the nanozyme hydrogel composite dressing in bactericidal and anti-inflammatory. The nanozyme hydrogel composites can transform M1 macrophages into M2 macrophages and eliminate ROS and bacteria (by biorender).

The prevailing strategies for myocardial infarction therapy primarily concentrate on restoring myocardial blood supply, often overlooking the intricate microenvironment characterized by heightened levels of reactive oxygen species (ROS) accompanying myocardial infarction. This milieu entails cardiomyocyte apoptosis, significant vascular cell death, excessive inflammatory infiltration, and fibrosis. In response to this challenge, He et al. (Hu et al., 2023) introduce a zinc-based nanozyme injectable multifunctional hydrogel, fabricated from ZIF-8, to counteract ROS effects following myocardial infarction. The hydrogel demonstrates both superoxide dismutase (SOD)-like and catalase (CAT)-like enzymatic activities, efficiently eliminating excess ROS in the infarcted area and interrupting ROS-driven inflammatory cascades. Moreover, the hydrogel’s remarkable immunomodulatory capability facilitates a notable shift of macrophages toward the M2 phenotype, effectively mitigating inflammatory mediators and indirectly promoting vascularization in the infarcted region. Given the high ROS levels and zinc demand within the infarcted microenvironment, the gradual release of zinc ions as the hydrogel degrades further enhances the bioactivity and catalytic performance of the nanozymes, synergistically promoting cardiac function post-myocardial infarction. In summary, this approach of integrating catalytic nanomaterials into bioactive matrices for ROS-related ailment therapy not only lays a robust foundation for biomedical material advancement but also offers a comprehensive strategy for addressing the complexities of myocardial infarction.

Dry eye disease (DED) is a common multifactorial ocular surface condition that impacts the daily functioning of millions of individuals globally. Although the pathogenesis of DED, a multifactorial inflammatory disease, is not yet fully understood, research has indicated a significant role of reactive oxygen species (ROS) in its development. Wei et al. developed a temperature-sensitive in situ gel system with incorporated C-dots nanozyme (C-dots@Gel) for controlled drug release. This system was formulated by embedding C-dots nanozyme into a temperature-responsive hydrogel via a swelling loading technique (Figure 4). The resulting composite drug delivery system exhibited strong adhesion to the corneal surface, extending ocular surface retention time and thereby enhancing bioavailability. In a DED mouse model induced by benzalkonium chloride (BAC), C-dots@Gel was shown to effectively mitigate DED symptoms. The mechanism involved stabilizing the tear film, prolonging tear secretion, repairing corneal surface damage, and increasing the number of conjunctival goblet cells. Importantly, no observable ocular surface irritation or systemic toxicity was detected.

Figure 4.

Schematic diagram of the C-dots@gel preparation and its effect on dry eye disease (DED). This study presents the development of a C-dots nanozyme thermosensitive in situ gel system (C-dots@Gel) for controlled drug release. Reprinted from (Wei et al., 2024) with permission from Taylor & Francis Group.

6. Conclusions and prospects

Some nanozyme-hydrogel composites are nontoxic, biodegradable, biocompatible and bioactive. Remarkably, the composite synergistically modulates drug release kinetics to achieve controlled and ‘on-demand’ drug release and remodels the pathological microenvironment to facilitate drug penetration. However, some intrinsic drawbacks of the composite hinder its further clinical translation. (1) The bological application of the composite is limited mainly to topical drug delivery because the composite exposed in the circulation system may cause thrombus and off-target effects (Xie et al., 2021). (2) When administered in the lumen, the hydrogel may cause obstruction due to its firm covalent structure, such as intestinal obstruction and ureteral obstruction (Zurita-Martínez et al., 2023). (3) The hydrogel in the composite prevents direct interactions between nanozymes and substrates, thereby decreasing the catalytic efficiency. (4) While nanozymes generally exhibit low toxicity, the long-term effects and potential for bioaccumulation require thorough investigation. The choice of metal or metal oxide nanoparticles can significantly influence toxicity levels. We can implement several optimizations to address potential issues such as thrombus formation and off-target effects. One approach is to fabricate the hydrogel into nano microspheres or nanoparticles, which can help mitigate thrombus formation and minimize off-target effects. To prevent obstruction resulting from the hydrogel, we can engineer the composites to self-degrade, thus avoiding lumen blockage. The catalytic efficiency of nanozymes can be affected by factors such as particle size, surface area, and the presence of functional groups that enhance substrate binding. Additionally, the microstructure of the hydrogel should be tailored to accommodate the size of the nanozymes and facilitate the passive diffusion pattern of substrates within the composite. This involves designing appropriate pores that allow the nanozymes to diffuse out and efficiently react with the substrate. Optimizing these parameters is essential for achieving high catalytic performance. Overcoming the current limitations and addressing safety concerns are essential steps toward the clinical translation of nanozyme-hydrogel composites. Continuous research and development are required to bring these advanced materials from the laboratory to clinical practice.

Funding Statement

This research was funded by the National Natural Science Foundation of China [82300868], Medical Technology Plan of Zhejiang Province [grant number: 2022497314], the Natural Science Foundation of Zhejiang Province [grant number: LQ21H160041], the Natural Science Foundation of Zhejiang Province [grant number: LBQ20H050001].

Author contributions

HL and ZL were responsible for the conception, charting, and first draft of this paper. PZ and DZ were responsible for the conception, critical revision, and final approval of this paper. All authors agree to be accountable for all aspects of the work.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.