Nanozymes as next-generation ROS scavengers: design strategies, catalytic mechanisms, and therapeutic frontiers

Abstract

Reactive oxygen species (ROS) play a dual role in human physiology, acting as essential signaling molecules at physiological levels while driving oxidative damage and disease pathogenesis when overproduced. This review systematically examines the molecular mechanisms of ROS-induced tissue injury and the evolution of antioxidant materials. Conventional antioxidants and emerging nano-antioxidants are discussed here, with particular focus on nanozyme-engineered nanomaterials mimicking natural enzyme activities. This article details design strategies for metal-based, carbonaceous, and polymeric nanozymes, their catalytic ROS scavenging mechanisms (including superoxide dismutase-, catalase-, and peroxidase-like activities), and therapeutic applications in inflammatory diseases, organ protection, and chronic disorders. Through a comparative analysis of material performance and biological effects, we highlight the advantages of nanozymes in terms of stability, multifunctionality, and targeted delivery. Current challenges regarding biocompatibility optimization, in vivo fate prediction, and clinical translation are critically discussed. This work provides strategic insights for developing next-generation antioxidant nanomaterials with enhanced therapeutic precision and safety profiles.

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1. Introduction

Reactive oxygen species (ROS), primarily defined as oxygen-derived single-electron reduced metabolites, encompass a hydroxyl radical (˙OH), hydrogen peroxide (H₂O₂), singlet oxygen (¹O₂), a superoxide anion (O₂˙⁻), etc., which play dual regulatory roles in human physiology and pathology.¹ ROS can serve as essential secondary messengers at low doses in cell signaling pathways, mitotic responses, cell proliferation/migration/differentiation, and the body's defense against pathogen invasion. Conversely, high levels of ROS easily cause DNA damage, lipid peroxidation, oxidative damage, and protein denaturation to other biomolecules, ultimately culminating in cellular apoptosis and tissue degeneration.

Clinical evidence has established a direct correlation between ROS overproduction and the pathogenesis of diverse inflammatory disorders. Excessive ROS generation initiates a vicious cycle of oxidative stress amplification, exacerbating tissue injury in conditions ranging from acute trauma (wound sepsis and organ ischemia–reperfusion) to chronic inflammatory pathologies (inflammatory bowel disease, hepatic fibrosis, and atherosclerosis).² Notably, emerging research implicates sustained ROS elevation as a key driver of chronic disease progression through persistent oxidative damage accumulation and aberrant redox signaling.

Current antioxidant strategies employ two distinct material paradigms: traditional antioxidant materials and novel antioxidant nanomaterials. Traditional antioxidant materials include natural products and synthetic small molecule organic compounds. They function through the antioxidant enzyme system, or by electron transfer (ET), proton transfer (PT), hydrogen atom transfer (HAT), etc. to scavenge free radicals, or directly react with ROS, etc., thereby reducing the damage of free radicals to cells. The advent of nanotechnology has revolutionized this field through engineered nanomaterials exhibiting enhanced ROS scavenging capabilities, including carbon-based nanomaterials, metal–organic frameworks (MOFs), metal nanoparticles, metal oxide nanostructures, quantum dots, polymers, nanozymes, etc. Among them, in recent years, nanozymes have attracted plenty of focus owing to their distinctive benefits, which include simple preparation, affordability, high stability, and easy storage.

This review comprehensively discusses ROS-mediated pathophysiological mechanisms and critically evaluates current antioxidant material systems. Special emphasis is placed on nanozyme innovations, analyzing their design principles, catalytic mechanisms, and therapeutic applications. This article first deeply delineates ROS generation/elimination dynamics and their pathophysiological implications. Subsequently, according to the characteristics of the materials, various existing antioxidant materials are classified, and their characteristics and applications as antioxidants are discussed. This review highlights recent breakthroughs in nanozyme engineering for ROS modulation, concluding with an outlook on antioxidant material design challenges and translational opportunities in precision nanomedicine (Scheme 1).

Scheme 1 Classification of antioxidant nanomaterials and disease applications.

2. The dual role of ROS in disease pathogenesis

2.1 ROS generation

Organisms can produce ROS through endogenous or exogenous pathways. The endogenous pathway involves the action of cyclooxygenase or xanthine oxidase in the respiratory chain of the mitochondria, cytochrome P450 (CYP450), endoplasmic reticulum stress, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), etc.;³ the exogenous pathway encompasses environmental factors, such as air particulate matter, chemicals, ionizing radiation, heavy metals and drug stimulation, that disrupt cellular redox homeostasis.

2.2 ROS: physiological regulators vs. pathological mediators

Under homeostatic conditions, cells maintain ROS concentrations within a narrow physiological range through sophisticated antioxidant systems comprising enzymatic (e.g., glutathione peroxidase, superoxide dismutase, and catalase) and non-enzymatic (e.g., ascorbic acid and glutathione) components. At these basal levels, ROS is considered a lethal defense molecule released by neutrophils to destroy exogenous pathogens invading the human body without causing a disordered inflammatory response. Furthermore, ROS can act as an intracellular signaling molecule, mediating various biological activities such as migration, gene expression, differentiation, and cell division. A moderate amount of ROS promotes the recruitment of inflammatory cells and initiates the healing procedure.

However, when the ROS homeostasis is disrupted, ROS accumulation occurs when production overwhelms antioxidant capacity, establishing a state of oxidative stress and causing chronic tissue damage. Proteins, nucleic acids, and lipids are examples of biological macromolecules that will be damaged by excessive ROS. Such molecular lesions initiate various chronic tissue injuries and degenerative processes.⁴

2.3 ROS and diseases

Mounting evidence implicates ROS dysregulation in the pathogenesis of diverse disorders, including inflammatory diseases, neurodegenerative diseases, cardiovascular diseases, metabolic system diseases, immune system diseases, etc.

The most prevalent degenerative joint disease, osteoarthritis (OA), is demonstrated by an imbalance between the body's antioxidant defense system (oxidative stress) and reactive oxygen species generation. In the cartilage of osteoarthritis patients, the level of oxidative stress is often high. The joint fluid has a markedly elevated level of inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6).⁵ These inflammatory factors not only promote the generation of ROS but also enhance the activity of matrix-degrading enzymes, ultimately leading to the destruction of the cartilage extracellular matrix and the loss of joint functions.

The central nervous system (CNS) exhibits particular vulnerability to ROS in accordance with high oxygen consumption (20% of total body intake), abundant polyunsaturated lipids (60% of brain fatty acids), and relatively low antioxidant reserves. In Alzheimer's disease, Aβ42 oligomers induce NADPH oxidase-mediated ROS production, which facilitates tau hyperphosphorylation and promotes necroptosis through RIPK1 activation. Parkinsonian models demonstrate dopamine autoxidation-generated semiquinones that deplete glutathione stores, exacerbating α-synuclein aggregation.

In cardiovascular diseases, ROS and ROS-related proteins can act as damage-associated molecular pattern molecules (DAMPs) to activate NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasomes. Previous studies have shown that there is a connection site between mitochondria and the endoplasmic reticulum, called mitochondrial-associated membranes (MAMs). MAMs have a variety of functions in the development of cardiovascular illnesses, but the most crucial one is their capacity to inhibit ROS generation, which further stimulates the NLPR3 inflammasome and accelerates the course of the disease.⁶

Malignant diseases (like breast cancer and colon cancer), chronic inflammatory diseases (like chronic pulmonary obstructive disorder and diabetes), autoimmune diseases (like rheumatoid arthritis), neurodegenerative diseases (like Parkinson's disease), cardiovascular diseases (like atherosclerosis), and other conditions are also brought on by ROS. It is evident that ROS are essential to the etiology of numerous illnesses, and their excessive production is associated with various pathological processes. Therefore, drugs and new materials that can effectively scavenge ROS are crucial for illness treatment and prevention.

3. Antioxidant materials

Due to the important role of ROS in many diseases, antioxidant materials have been given an enormous amount of attention lately. By scavenging ROS, antioxidant materials primarily reduce the amount of oxidative stress in the body and avert the development of numerous ailments. They can capture free radicals and protect cells by forming stable substances, reducing the damage to cells. In addition, antioxidant materials also have anti-inflammatory effects and can slow down the inflammatory response to help treat inflammatory diseases. According to the nature and characteristics of the materials, antioxidant materials are divided into two categories: traditional antioxidant materials and novel antioxidant nanomaterials.

3.1 Traditional antioxidant materials

3.1.1 Natural products. Natural antioxidants mainly include polyphenols, carotenoids, vitamins, natural enzymes, amino acids, polysaccharides, flavonoids, etc. Owing to their natural origin, these compounds generally exhibit high biocompatibility and are widely utilized in pharmaceuticals and nutraceuticals. However, some of them have inherent defects, such as poor solubility, unstable or excessively rapid metabolism within the body. These defects greatly limit their bioavailability and practical applications (Table 1).

Table 1 Classification of natural antioxidant materials with advantages, limitations, and applications

Materials	Advantages	Disadvantages	Applications	Ref.
Polyphenols	Strong free radical scavenging ability; high safety	Insufficient bioavailability	Food preservation; materials made of ultra-high molecular weight polyethylene that are very resistant to wear	7–9
Carotenoids	Multiple free radicals scavenging	Easily oxidized	Skin antioxidants; food packaging films	10 and 11
Vitamins	A wide range of antioxidant effects	Adverse reactions when consumed in excess	Antioxidants, immunomodulatory, anti-inflammatory, and neuroprotective abilities	12
Natural enzymes	High catalytic activity and selectivity	Low stability of the enzyme, significant demands on the environment for catalytic activity, difficult synthesis, and harsh purification conditions	Food preservation; diseases related to free radical damage	13
Amino acids	High bioavailability, easy to be absorbed and utilized by the body	May be relatively high cost	Treatment of cell damage related to oxidative stress; skin protection	14 and 15
Polysaccharides	Good antioxidant effects	Acidic conditions may affect product activity and have some limitations	Antioxidant, anti-inflammatory, and anti-freckle cosmetics	16
Flavonoids	Strong antioxidant effects	Difficult to absorb and utilize, and challenging to get through the blood–brain barrier	Prevention of Parkinson's disease; nutritional health products	17 and 18

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(i) Polyphenols: polyphenols, such as curcumin, gallic acid, resveratrol, tannic acid, and tea polyphenols, possess a multi-hydroxy structure connected to the benzene ring, making them effective antioxidants. They not only have a strong free radical scavenging capacity but can effectively decrease the response to oxidative stress and protect related tissues with high safety. However, their bioavailability is not high enough, limiting their applications.

(ii) Carotenoids: carotenoids, such as β-carotene and astaxanthin, contain multiple conjugated double bonds, which can react with free radicals to preserve biological molecules from oxidative damage, including proteins, DNA, and lipids found in cell membranes.¹⁹ They have strong antioxidant activity and can scavenge multiple free radicals. However, their stability needs to be managed to avoid oxidation during application.

(iii) Vitamins: vitamins, such as vitamin C, scavenge harmful oxygen free radicals, including O₂˙⁻, H₂O₂, and ˙OH through its reducibility and have a wide range of antioxidant effects. However, excessive intake of vitamin C may cause adverse reactions such as diarrhea and nausea. Vitamin E²⁰ can block the chain reaction of cell membrane lipid peroxidation and protect cells, tissues, and organs from free radical attacks. However, excessive vitamin E intake may increase bleeding risks.

(iv) Natural enzymes: natural enzymes, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GSHPx and Gpx), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PD), etc., are biological catalysts with high catalytic activity and selectivity that promote antioxidant reactions. However, due to the disadvantages such as low enzyme stability, high requirements for the catalytic activity environment, difficult synthesis, and harsh purification conditions, their practical applications are greatly limited.

(v) Amino acids: amino acids, like cysteine, glycine and glutamic acid, can react with free radicals through their side chain groups to neutralize free radicals and prevent them from damaging organisms.²¹ They have high antioxidant ability, can effectively reduce the production of free radicals and can preserve cells’ regular functionality. Amino acids have high bioavailability and are easy to be absorbed and utilized by the body. However, the cost of amino acids as antioxidants may be relatively high, especially in the food and medicine practical applications.

(vi) Polysaccharides: polysaccharides, such as pectin and chitosan, are long-chain carbohydrate polymers that help scavenge free radicals, inhibit lipid peroxidation, and protect biological membranes by boosting antioxidant enzyme activity.²² Despite their benefits, polysaccharides are susceptible to degradation, particularly during phosphorylation, and may lose activity under acidic conditions, which can limit their applications.

(vii) Flavonoids: the flavonoid structure's phenolic hydroxyl group is the main functional group for scavenging free radicals, which can enhance the activity of antioxidant enzymes SOD and CAT and the content of glutathione (GSH), thereby reducing the level of lipid peroxides in cells.²³ Quercetin is a natural flavonoid with antioxidant activity and is widely extracted from fruits and vegetables. Quercetin has strong antioxidant, anti-inflammatory, antibacterial, and angiogenic properties and can play a neuroprotective role by directly scavenging hydroxyl radicals and superoxide anions. However, due to hydrophobicity, it struggles to cross the blood–brain barrier, limiting its absorption and utilization.

3.1.2 Small molecule organic compounds. Small molecule organic compound antioxidants mainly include synthetic products such as metformin, lipoic acid, erythorbic acid, and sodium counterpart, and ascorbic acid. These antioxidants are often used in fields such as food, medicine, cosmetics, and rubber plastics due to their clear chemical structures and predictable stability to improve product stability and extend the shelf life. While small molecule organic compounds offer significant potential in antioxidant applications, they also face challenges in many aspects such as toxicity, cost, environmental impact, and synthesis efficiency.

(i). Metformin: metformin is a widely used hypoglycemic drug and has also garnered attention for its potential antioxidant properties. Metformin activates AMP-activated protein kinase (AMPK) and Nrf2 signaling pathways, among other molecular pathways, to produce antioxidant effects, inhibiting NADPH oxidase, restoring enzyme activity, and regulating inflammatory factors. By activating AMPK, metformin helps to mitigate inflammation and oxidative stress, thereby reducing cellular damage. Furthermore, through an AMPK-dependent pathway, metformin inhibits NADPH oxidase, decreasing oxidative stress. In addition, metformin can activate the Nrf2 signaling pathway, thereby inducing antioxidant genes’ expression such as SOD and GPx and enhancing the antioxidant capacity of cells. Metformin can selectively inhibit complex I in the mitochondrial electron transport chain to reduce the production of ROS. These mechanisms jointly contribute to the reduction of ROS production in different cell backgrounds and disease models.²⁴ However, a number of factors, including dosage, the duration of treatment, and other medical problems, influence how effective metformin is as an antioxidant intervention. Consequently, although metformin has potential in antioxidants, its benefits and risks need to be weighed in clinical use.

(ii) Lipoic acid: many studies have examined lipoic acid's in vitro and in vivo characteristics, particularly its antioxidant capacity as a metal chelator, free radical scavenger, and oxidative damage repair agent. Other related benefits of supplementing lipoic acid also include mitochondrial-related metabolic pathways, possible improvement of cell signaling associated with a coupling to endothelial nitric oxide synthase (eNOS), and anti-inflammatory properties. These factors make this substance an appealing antioxidant for diabetes-related conditions like neuropathy, retinopathy, and other vascular disorders. At the molecular level, the cells of mice treated with lipoic acid exhibit significantly lower levels of expression of extracellular matrix (ECM) proteins, fibrosis factors, inflammatory factors (transforming growth factor-β1 and monocyte chemoattractant protein-1), and epithelial-to-mesenchymal transition markers (E-cadherin and α-smooth muscle actin) than mice that were not treated.²⁵ However, some side effects may occur when using lipoic acid, such as palpitations, decreased thiamine levels, and hypoglycemia.

3.2 Novel antioxidant nanomaterials

Novel antioxidant nanomaterials primarily include nanoselenium, quantum dots, and polymers. These materials possess antioxidant activity, can scavenge free radicals, prevent lipid peroxidation or enhance the activity of antioxidant enzymes to shield tissues and cells from the damaging effects of oxidative stress. They have potential application prospects in fields such as medicine, food, health products, and treatment of inflammatory diseases, but further research and optimization are needed to overcome their limitations.

3.2.1 Nanoselenium. Nanoselenium can directly react with ROS in the body such as O₂˙⁻, ˙OH, H₂O₂ and nitric oxide radical (NO), converting these radicals into harmless substances, thereby reducing the damage of free radicals to cells and tissues.²⁶ In addition, nanoselenium can also participate in intracellular redox reactions, helping to regulate the intracellular redox state and maintain the balance of redox substances within cells. For instance, nanoselenium has the ability to modulate the levels of GSH within cells. GSH is a critical antioxidant, and by sustaining its levels, nanoselenium effectively boosts the cellular antioxidant capacity, thereby protecting cells from oxidative stress However, when nanoselenium exists alone, it is easy to agglomerate, resulting in an increase in particle size, a decrease in biological activity, and even may be converted into inactive gray selenium. This agglomeration phenomenon limits its application in fields such as food, medicine, and health products.

3.2.2 Quantum dots. Most quantum dots are not classified as nanozymes. They are primarily utilized in imaging and optoelectronic fields, but they may participate in redox reactions under specific conditions. As a case in point, black phosphorus quantum dots (BPQDs) are a low-dimensional nanomaterial prepared by a simple one-step method and have completely controllable biodegradability and great potential. This study²⁷ comprehensively explored the extensive free radical scavenging ability of BPQDs and emphasized their great potential in treating ROS-related organ damage. BPQDs can simultaneously scavenge DPPH, ABTS˙, OH˙, and O₂˙⁻, and even at a very low dose, they can show good cell protection against ROS-mediated damage. However, owing to their large specific surface area and high surface energy, quantum dot nanomaterials are easy to agglomerate, which will reduce their effective specific surface area, thereby affecting their antioxidant performance and the interaction effect with other substances.

3.2.3 Polymers. Antioxidant polymers are functional materials that inhibit free radical damage and oxidative stress and used in drug delivery, tissue engineering, and disease treatment, with the potential to enhance biocompatibility and therapeutic efficacy. As a case in point, polydopamine (PDA) as a typical melanin analogue has attracted attention due to its excellent biocompatibility and antioxidant activity. PDA is anticipated to be used in the therapy of numerous inflammatory illnesses because it has the ability to scavenge various free radicals in cells and tissues.²⁸ The antioxidant mechanism involves the impact of electron delocalization in the plane of the oligomers within its microstructure, as well as the redox characteristics of catechol, enabling it to scavenge various free radicals. However, the duration of its antioxidant activity is limited. PDA's phenolic hydroxyl groups primarily scavenge free radicals, that is, how it might have antioxidant effects over time. However, as the reaction emerges, phenolic hydroxyl groups will be gradually consumed. Specifically, when exposed to a high-concentration free radical environment for a long time, the antioxidant active sites of PDA will continuously decrease, resulting in a gradual decline in its antioxidant capacity.

3.3 Antioxidant nanozymes

A category of nanomaterials known as nanozymes closely resembles genuine enzymes in their catalytic characteristics and enzyme-like kinetic behaviors. They are capable of catalyzing the same substrates as natural enzymes, producing catalytic reactions that mimic those of their biological counterparts. Nanozymes differ from natural enzymes in that they are more stable, and have variable activity and high recovery efficiency, which help to improve safety in use, disposal, and disease monitoring. They show an abundance of potential to address the drawbacks of natural enzymes, such as their high cost and storage challenges. Redox nanozymes are the most studied among the six major types of enzymes currently. They can be classified into metal and metal oxide nanozymes, metal–organic framework (MOF)-derived nanozymes, carbon-based nanozymes, etc. according to their compositions. Given their distinct physicochemical characteristics and great catalytic effectiveness, these redox nanozymes offer a wide range of potential applications in fields like chemical engineering, medicine, and the environment. By changing the size, structure, components, and surface modification of nanomaterials, their catalytic activities can be adjusted, showing great application potential (Table 2).

Table 2 Categories of antioxidant nanozymes and their representative references

Materials		Advantages	Disadvantages	Chronic disease applications	Ref.
Metal and Metal oxide	Au	High bioavailability and good physical and chemical stability	Greatly affected by environmental factors; long-term stability is not good	AKI	29 and 30
				Anti-aging
	Ag	Good stability; easy to prepare and modify	Potential biological toxicity; high cost	Wound healing Antibacterial Antioxidant	31 and 32
	Pt	High catalytic activity; strong adjustability	Difficulties in preparation and quality control	AKI	33
	IONPs	Multiple antioxidant mechanisms; advantages brought by magnetic properties	Stability problems	Gouty arthritis	34 and 35
				Inflammatory bowel disease
	CeO2	Excellent chemical stability and a high capacity to scavenge free radicals	The bioavailability and distribution in organisms are relatively complex	Chronic kidney disease	36–38
				Wound healing
				Diabetic kidney disease
	MnO2	Good chemical and thermal stabilities	Difficulties in optimizing and evaluating antioxidant performance	Preventing postoperative adhesion	39 and 40
				Inflammatory skin diseases
MOFs	ZIF	Relatively high structural stability; adjustable chemical composition is beneficial to antioxidant design	Potential sensitivity of metal ions	Parkinson's disease Senile osteoporosis	41 and 42
	UIO	High structural stability; stability of the metal center	Challenges in long-term stability	Tumor recurrence	43–45
				Thrombolytic therapy
				Atherosclerosis
	MIL	Structural diversity; the potential antioxidant properties of metal nodes	Fragility of organic ligands	Ischemic stroke	46
Carbon-based nanozyme	GO	High free radical scavenging ability	Stability problems (affected by environmental factors)	Myocardial regeneration	47 and 48
				Rheumatoid arthritis
	C60	Good light and chemical stabilities	Poor solubility; relatively high preparation cost	Diabetes	49
	CDs	High reactive oxygen species scavenging ability	Environmental dependence of antioxidant performance	Diabetic foot ulcer	50–52
				Osteoarthritis
	CNTs	High catalytic activity; recyclable	Complicated preparation process and high cost	Alzheimer's disease	53
				Rheumatoid arthritis

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3.3.1 Metal and metal oxides. Metal nanozymes encompass noble metal nanoparticles, including gold (Au), silver (Ag), and platinum (Pt). In catalytic reactions, there is no change in the valence state of metal elements. Instead, they play a role through adsorption, activation, and surface electron transfer.⁵⁴ Transition metal oxide nanoparticles,⁵⁵ including iron oxide nanoparticles (IONPs), cerium oxide (CeO₂) nanoparticles, and manganese oxide (MnO₂) nanoparticles. Based on their ability to mimic enzymes, CeO₂ nanoparticles have garnered plenty of interest in biological research.⁵⁶ They exhibit redox enzyme activity by integrating nanozymes and substrates to generate valence state changes and electron transfer. Compared with natural enzymes, metal and metal oxide nanozymes have better thermal stability, acid–base stability, and storage stability. They are able to sustain consistent catalytic activity in a broad temperature range, pH values, and different chemical environments and are not easily denatured and inactivated due to changes in environmental conditions. This makes them more advantageous in some complex practical application scenarios. However, nanozymes usually lack the highly specific substrate recognition and binding ability of natural enzymes and have relatively low substrate selectivity. They may catalyze the reactions of multiple substrates with similar structures, resulting in lower reaction specificity and accuracy than natural enzymes. In some applications such as biological analysis and medical diagnosis with high selectivity requirements, interference may occur.

3.3.2 MOF materials. MOFs are a particular type of organic–inorganic hybrid porous material that self-assembles from inorganic metal centers (metal ions or metal clusters) and organic ligands. They have a periodic network structure. The properties of MOF materials include the large specific surface area, ordered porous structure, unique chemical composition, and changeable structure.⁵⁷ Furthermore, MOFs have intrinsic enzyme-like activity due to their high metal center content and ease of modification. As a case in point, UIO-66 belongs to zirconium-based MOFs. It has a highly ordered porous structure formed by connecting zirconium ions (Zr⁴⁺) with organic ligands (usually terephthalic acid) through coordination bonds to form a three-dimensional crystal framework. The pore structure of UIO-66 can selectively adsorb ROS such as O₂˙⁻, ˙OH and H₂O₂. By physical adsorption, these highly oxidizing ROS are fixed in its pores, reducing their concentration in the surrounding environment and reducing the probability of oxidation reactions.⁵⁸ Zeolitic imidazolate framework (ZIF) materials are three-dimensional porous crystals that self-assemble from imidazole organic ligands via coordination bonds and transition metal ions (e.g., Zn²⁺ and Co²⁺). As a case in point, ZIF-8 (a common ZIF material composed of Zn²⁺ and 2-methylimidazole), the zinc ions and imidazole ligands in its structure may react with active oxygen radicals such as ˙OH and O₂˙⁻ by providing electrons;⁵⁹ MIL (materials of institute Lavoisier) is a material formed by metal ions (such as Cr³⁺ and Fe³⁺) and organic ligands through coordination bonds. As a case in point, MIL-101, the metal center can act as an electron donor, when encountering a hydroxyl radical, the oxidation state of the metal ion may change. By providing electrons, the hydroxyl radical is reduced, thus realizing the scavenging of free radicals. At the same time, the organic ligand may also participate in the reaction. It has functional groups that can interact with free radicals and supply electrons, like phenolic hydroxyl groups. Through this interaction, the organic ligand itself gets oxidized, effectively scavenging the free radicals and contributing to the overall antioxidant activity.⁶⁰ However, most MOF materials have the disadvantages of poor water stability and thermal stability, which means that they may lose structural integrity in a humid or high-temperature environment, affecting their antioxidant performance.

3.3.3 Carbon-based nanozymes. Carbon dots (CDs), fullerenes (C₆₀), graphene oxide (GO), carbon nanotubes (CNTs), and their doped derivatives or composites are the primary components of carbon-based nanozyme materials. Due to their unique electronic structures and surface properties, they exhibit activity in catalytic redox reactions.⁶¹ As an illustration, Song et al. synthesized single-walled carbon nanotubes with peroxidase (POD)-like activity to identify illnesses linked to single nucleotides. As there is H₂O₂ present, magnetic NPs with multi-walled carbon nanotubes were prepared to simulate the POD-catalyzed oxidation of TMB. Although natural enzymes are easily denatured and inactivated in the external environment, carbon-based nanozymes are relatively stable. Under some severe circumstances, nevertheless, they might still become inactive (e.g., extreme temperature, acute acid, and the strong alkali environment). The environmental impact and potential toxicity of carbon-based nanozymes also need to be considered. Especially, in biomedical applications, their long-term effects and safety need further research and evaluation.

Although the above redox nanozymes have broad application potential in many fields, there are also some limitations and challenges, including tissue targeting, material stability, unclear catalytic mechanism, unclear biological safety and potential toxicity, low catalytic activity and selectivity, etc., which require more in-depth exploration.

3.4 Traditional materials vs. nanozymes

Traditional materials have played a certain role to some extent, but nanozymes have more advantages and development space. Table 3 demonstrates the nanozymes’ advantages: superior catalytic efficiency (enzyme-like activity), enhanced stability (reusable potential), and multifunctionality vs. traditional materials’ limitations. While cost-effective at scale, traditional materials pose biodurability risks (organ accumulation and fibrosis). Nanozymes mitigate this via controllable retention (size/charge modulation).

Table 3 Comparison between traditional materials and nanozymes

Comparison dimension	Traditional materials	Nanozymes
Catalytic performance	Depending on the intrinsic properties of materials, with a single active component and relatively low efficiency.	Enzyme-like activity and high catalytic efficiency
Stability	Long-term storage is prone to inactivation	Some parts can be reused
Functional diversity	Single function	Multi-functional integration and strong designability
Cost	Low costs in mass production	Low usage and high efficiency
Biodurability	Refractory materials can accumulate in organs (liver and spleen) for a long time, causing fibrosis	Controllable retention of nanozymes: reduce the accumulation risk through size/charge modulation.

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4. Antioxidant nanozymes with multiple enzyme activities

Since the structure of nanozymes is directly related to their enzyme activities, the types and numbers of active sites in the structure directly determine the enzyme performance of nanomaterials. Some carefully designed nanomaterials can have multiple active sites and exhibit multiple enzyme activities. Compared with single-enzyme nanozymes, multi-enzyme nanozymes have unique advantages such as synergy, cascade reactions, and environmental selectivity. Nanomaterials’ numerous enzyme activities can enhance the therapeutic effect by simulating the combined action of multiple enzymes in biological systems.

4.1 Enhancement of catalytic efficiency by multiple enzyme activities

Antioxidant nanozymes with several enzyme activities not only have the activities of simulating multiple natural antioxidant enzymes (such as CAT, SOD, GPx, etc.), but also these different enzyme activities can cooperate and promote each other, producing a more significant antioxidant effect than the simple addition of single enzyme activities or multiple enzyme activities. Such nanozymes usually have unique nanostructures and chemical compositions, enabling them to efficiently perform multiple antioxidant functions in the same system. The effect of designing multiple enzyme active sites can be achieved by mixing the same element of metal nanozymes in different valence states or doping multiple elements.

Accordingly, oxidative stress and bacterial infection are two major problems in the healing of chronically infected wounds. To destroy bacteria and get rid of free radicals, molybdenum disulfide nanosheets (MoS₂ NSs) with triple enzyme-like capabilities are loaded onto carbon nanotubes (CNTs) and combined with a multifunctional hydrogel (Fig. 1A). The hydrogel's strong antibacterial qualities are a result of its increased POD-like activity in acidic environments, as well as the combination of GSH depletion and photothermal treatment (PTT). Additionally, the hydrogel has remarkable antioxidant qualities because of its CAT and SOD-like activities, its capacity to scavenge ˙OH, and its capacity to remove reactive nitrogen species (RNS) in a neutral environment.⁶²

Fig. 1 (A) (a) Hydrogel preparation. (b) An overview of dual-enhanced triple nanozyme activities with CNTs and NIR, and (c) the mechanism behind wound healing. Reproduced from ref. 62 with permission from John Wiley and Sons Ltd, copyright 2021. (B) Manganese spinel oxide valence engineering is being used to create self-cascading antioxidant nanozymes for improved treatment of IBD. Reproduced from ref. 63 with permission from John Wiley and Sons Ltd, copyright 2022. (C) An ultrasmall RuO₂ nanozyme for the prevention of acute kidney injury is shown schematically. Reproduced from ref. 64 with permission from American Chemical Society, copyright 2020. (D) Multiple enzyme-like properties for non-toxic removal of ROS. O_v: oxygen vacancies. Reproduced from ref. 65 with permission from American Chemical Society, copyright 2023.

ZnMnO₄ (abbreviated as ZM) exhibits just SOD-like activity (single antioxidant activity) in inflammatory bowel disease. With the gradual doping of Li, Mn increases from a valence of 3 to 4, and the nanozyme not only has improved SOD-like activity but also gradually enhanced CAT-like and GPx-like activities. Finally, the optimized nanozyme LiMn₂O₄ (named LM) simultaneously has the best SOD, CAT, and GPx-like activities and has the ability to scavenge hydroxyl radicals (Fig. 1B). The obtained LM exhibits good antioxidant and therapeutic effects at the cell level and in an inflammatory bowel disease (IBD) model.⁶³

To prevent acute kidney injury (AKI), an ultrasmall RuO₂ nanozyme with good biocompatibility and enzyme-like activity was designed. The picture illustrates how the multi-enzyme-like (CAT, SOD and GPx) properties of the ultrasmall RuO₂ NPs make them suitable for use as antioxidants. According to the results of the in vitro experiments, ultrasmall NPs significantly reduce kidney damage caused from oxidative stress. An AKI mouse model was used to investigate the ultrasmall RuO₂ nanozyme's in vivo therapeutic efficacy (Fig. 1C). The in vivo tests demonstrated that the NPs’ effective renal accumulation, renal clearance, and long-term biosecurity were all attributed to their minuscule size.⁶⁴ These ultrasmall RuO₂ NPs’ exceptional characteristics emphasize its potential as multi-enzyme-like nanozymes to prevent AKI.

An Au@Cu₂O structure with multi-enzyme-like activity was designed. Employing a multi-enzyme mimic, Au@Cu₂O can remove ROS in a neutral environment (like the cytoplasm) without causing harm (Fig. 1D). Even in an acidic environment dominated by POD-like activity, the electron transfer between an electron donor such as nicotinamide adenine dinucleotide phosphate (NADH) or GSH and H₂O₂ promotes the decomposition of H₂O₂ instead of forming ˙OH. Consequently, Au@Cu₂O can eliminate ROS (such as H₂O₂, O₂˙⁻, and ˙OH) through numerous enzyme activities, establishing a comprehensive antioxidant system, even in a complex and changing intracellular environment.⁶⁵

Some scholars have also summarized that these nanoscale materials present a promising new approach to ocular antioxidant therapy by simulating the functions of natural enzymes involving GPx, CAT, and SOD.⁶⁶

The synergy can make the combination of different enzyme activities on nanozymes produce an effect of 1 + 1 > 2, which will more efficiently scavenge ROS and free radicals and shield cells from oxidative damage. The synergy of multiple enzyme activities can accelerate the reaction rate and improve the treatment effect. Moreover, due to the improvement of nanozyme efficiency by synergy, the required treatment dose may be reduced, thereby reducing the burden on patients and the potential risk of toxicity.

4.2 Construction of cascade catalysis

Cascade catalysis refers to a series of catalytic reactions occurring successively in a reaction system, where the product of the previous reaction serves as the substrate for the next reaction. In the antioxidant nanozyme cascade catalysis system, multiple nanozymes or nanozymes and other molecules cooperate with each other to scavenge harmful substances such as ROS through continuous catalytic reactions. Cascade reactions have the characteristics of high local reactant concentration, low intermediate decomposition, and high mass transfer efficiency, which greatly improve the catalytic efficiency. Therefore, such nanozymes can achieve more significant treatment effects in treating diseases and even reduce the dosage.

As a case in point, a calcium gallate nanozyme with multi-enzyme catalytic activity was constructed by combining gallic acid with calcium ions to treat acute wounds. The CaGA nanozyme exhibits substantial antioxidant activity in vitro and significant superoxide CAT/SOD catalytic activity (Fig. 2A). The primary antioxidant enzyme, SOD, catalyzes the conversion of O₂˙⁻ into O₂ and H₂O₂ under healthy conditions. CAT then transforms these into non-toxic H₂O and O₂. SOD and CAT's cascade catalytic activity can shield organisms from excessive ROS damage.⁶⁷

Fig. 2 (A) (a) Diagram showing how CaGA nanozymes are synthesized. (b) An illustration shows how acute wounds are treated. Reproduced from ref. 67 with permission from Royal Society of Chemistry, copyright 2025. (B) SOD&Fe₃O₄@ZIF-8 NPs’ production pathway, multi-enzyme mimicking properties, and analgesic mechanism of anti-oxidative and anti-inflammatory effects on inflammatory pain are shown schematically. Reproduced from ref. 68 with permission from Wiley, copyright 2023.

In addition, to synthesize the antioxidant cascade nanozyme SOD&Fe₃O₄@ZIF-8 (SFZ), several researchers also investigated a straightforward co-assembly technique to simultaneously encapsulate SOD and Fe₃O₄ NPs in ZIF-8 NPs. Through intrathecal injection, this nanozyme can decrease the inflammatory factor acetylcholine and the unintended release of ROS in inflammation-activated glial cells. SFZ NPs can break down in a mildly acidic inflammatory environment during the spinal cord's inflammatory response, releasing the loaded SOD and Fe₃O₄ NPs, which are then taken up by inflammatory cells (Fig. 2B). Afterwards, through a cascade catalytic reaction driven by SOD and Fe₃O₄, the ROS (O₂˙⁻) generated by inflammatory cells is transformed into H₂O₂ and O₂, lowering central sensitization and glial cell oxidative damage.⁶⁸

There are also many examples of cascade nanozymes with SOD-CAT-like activities. For instance, a study constructed an ultrasmall (6–8 nm) Pt nanozyme loaded mitochondria-targeted liposome (Pt@MitoLipo) to alleviate hypoxia and eliminate excess ROS for effective retinal neovascularization disease therapy.⁶⁹ Copper-containing layered double hydroxide (Cu-LDH) nanozymes combined with nitric oxide-releasing molecules (GSHNO) generate Cu-LDH@GSHNO, a novel therapeutic strategy designed to counteract oxidative stress in the retinal vascular system.⁷⁰ Here, a Pt@PCN222-Mn integrated cascade nanozyme formulation is created to get rid of too much reactive oxygen species (ROS). The cascade nanozyme is an effective treatment for ulcerative colitis and Crohn's disease, two types of inflammatory bowel diseases (IBD).⁷¹ Finally, a study demonstrates that cerium oxide (ceria) nanorods, called “AHT-CeNRs,” which are produced by a sol–gel process with heat treatment, are an effective intracellular ROS scavenger. The produced AHT-CeNRs demonstrated remarkable CAT and SOD-like activities, both of which are essential for transforming ROS into innocuous byproducts.⁷²

4.3 Environmental selectivity

Antioxidant nanozymes with environmental selectivity refer to nanozymes whose antioxidant activity can change according to specific factors in the surrounding environment (such as the pH value, temperature, and specific ion concentration). This selectivity enables them to play a more precise antioxidant role in a complex and variable physiological environment.

CeO₂'s multi-enzyme-mimicking activity was easily controlled chemically at various synthesis temperatures. A notable change in CeO₂'s multi-enzyme-mimicking activity was noted at multiple synthesis temperatures. This regulation is the result of the combined action of the type and size of oxygen and the self-recovery ability of CeO₂ (Fig. 3A). The results showed that, at a particular synthesis temperature, high-performance CeO₂ may be logically built, and the rules derived from radar chart analysis may facilitate the application of cerium-based nanozymes in biomedicine.⁷³

Fig. 3 (A) Synthesis of ceria nanozymes via temperature regulation to optimize the multi-enzyme-mimicking activity for biomedical applications. Reproduced from ref. 73 with permission from Royal Society of Chemistry, copyright 2021. (B) Mechanism of adaptive ROS generation/scavenging and healing promotion in mouse wounds infected with bacteria and treated with LCDs-OA@CaO₂. Reproduced from ref. 74 with permission from Elsevier, copyright 2024.

As an instance, using a hydrothermal organic acid co-treatment method, a biocompatible lignin-based carbon dot nanomaterial (LCDs-OA) with more CO and COOH functional groups on the surface was developed and employed as a dual-enzyme-like activity nanozyme to treat bacterially infected diabetic foot ulcer (DFU) wounds (Fig. 3B). The results demonstrated that POD-like activity occurs in the bacterial infection microenvironment (BME) with a low pH (4.5–6.5), and that the activity progressively diminishes as the pH increases, which can catalyze H₂O₂ to generate the ROS hydroxyl radical (˙OH) to kill DFU bacteria. In the pH range of 6–10, it has a gradually enhanced CAT-like activity, decomposing ROS (H₂O₂) into H₂O and O₂.⁷⁴

5. Conclusions and perspectives

Given the significant correlation between ROS and diverse pathologies, this article provides a systematic review of advancements in antioxidant materials. It comprehensively examines the mechanisms, applications, and limitations of various antioxidant systems, including natural antioxidants, small-molecule synthetic antioxidants, and emerging antioxidant nanomaterials like carbon-based nanomaterials, metal nanoparticles, metal oxide nanomaterials, quantum dots, polymers, and antioxidant nanozymes. Despite technological progress and notable breakthroughs in antioxidant material research, several challenges remain unresolved.

Mechanistic understanding of antioxidant nanozymes: the catalytic mechanisms underlying antioxidant nanozymes require further investigation. Even while ROS scavenging has been the subject of several experimental investigations and theoretical computations, little is known about the underlying mechanisms. Modulating the catalytic activity of antioxidant nanomaterials requires an understanding of their catalytic kinetics and processes. Therefore, future research should prioritize mechanistic exploration to address these gaps.

Design optimization of antioxidant nanozymes: enhancing the catalytic efficiency of antioxidant nanozymes hinges on the rational design of their spatial structures and active centers. Although catalytic performance can be enhanced by imitating the structural characteristics of natural enzymes, high catalytic efficiency is still difficult to achieve. A nanomaterial's composition, size, shape, and crystal surface characteristics all affect its catalytic activity. Thus, a comprehensive analysis of material structural characteristics is critical for optimizing ROS scavenging capabilities. Furthermore, the design of accurate atomic and molecular structures can be facilitated by careful material selection, which will ultimately boost catalytic efficiency.

Biosafety and toxicity considerations: the potential toxicity and biosafety concerns associated with nanomaterials pose significant challenges. It is essential to conduct an exhaustive evaluation of antioxidant nanozymes’ biological safety. Consequently, material design must prioritize the development of antioxidant systems with high biocompatibility to ensure safe biomedical applications.

Balancing ROS levels for physiological functions: low concentrations of ROS play a vital role in biological processes, serving as key signaling molecules that regulate physiological functions such as inflammatory responses and metabolism. Therefore, the objective of ROS-scavenging biomaterials should be to maintain ROS levels within a physiological balance rather than eliminating them entirely. Excessive ROS removal may disrupt normal biochemical processes and cause adverse effects. Post-application monitoring of ROS-mediated physiological pathways is essential to ensure biosafety and therapeutic efficacy.

Data availability

This is a review article without any original data.

Conflicts of interest

The authors declare no competing financial interest.

Acknowledgements

This work was financially supported by the Natural Science Foundation of Shandong Province, China (ZR2022QE133) and the Opening Project of Hubei Key Laboratory of Cognitive and Affective Disorders (HBCAD2024-11).

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