Platinum nanozymes pursue cellular redox homeostasis: playing dual roles as pro-oxidants and antioxidants

Cellular redox homeostasis, essential for physiological integrity, is disrupted by pathological oxidative stress from imbalanced reactive oxygen species (ROS) metabolism, which is a central driver of degenerative, inflammatory diseases and tumors. Platinum (Pt) nanozymes have emerged as promising therapeutic agents capable of mimicking both antioxidative and pro-oxidative enzymatic activities, owing to their partially filled d-orbitals and accessible multivalent states, thereby enabling precise regulation of cellular redox homeostasis. From a chemical perspective, this “smart switching” capability originates from dynamic changes in microenvironmental cues, such as nanozyme concentration, H₂O₂ levels, and pH, which alter the dominant enzymatic activity, thereby achieving dual-mode ROS regulation by toggling between antioxidative and pro-oxidative states. This adaptive duality directly addresses a fundamental therapeutic dilemma: selectively restoring redox homeostasis in diseased tissue while sparing healthy cells. Therefore, this review systematically elaborates, for the first time, an integrated framework encompassing the intrinsic redox enzymatic activities of Pt nanozymes and their “smart switching” mechanisms, offering a cross-disciplinary perspective spanning material design to disease applications. First, we delineate evolving research trends and recent advancements in Pt nanozymes for redox homeostasis regulation through a bibliometric analysis of 512 publications from the Web of Science. Subsequently, we elucidate the catalytic mechanisms governing their tunable redox enzymatic activities and discuss versatile engineering strategies for tailoring antioxidant/pro-oxidant functionalities to enable precision therapeutic interventions. Finally, we critically evaluate current translational challenges and present future perspectives on addressing multifaceted disease pathologies using Pt nanozymes.

Graphical abstract

Supplementary Information

The online version contains supplementary material available at 10.1186/s12951-026-04387-1.

Highlights

1. A systematic review of the four key redox enzymatic activities of Pt nanozymes and their catalytic mechanisms is provided.

2. Strategies based on size, morphology, component doping, and surface modification to enhance the activity of Pt nanozymes are proposed.

3. The application progress and challenges of Pt nanozymes in over ten disease models, including inflammation, tumors, and neurodegenerative diseases, are summarized.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12951-026-04387-1.

Introduction

Reactive oxygen species (ROS) are oxygen-containing reactive chemicals including superoxide (O₂^•−), hydroxyl radical (•OH), hydrogen peroxide (H₂O₂), and singlet oxygen (¹O₂) [1]. A primary source is the unintended transfer of electrons from cellular metabolic pathways to O₂ [2]. Furthermore, NADPH oxidase family proteins in the cytoplasm and catalysis by trace amounts of transition metals in the body can also produce ROS [3, 4]. In addition to these endogenous sources, exogenous factors such as environmental stresses, accidental leakage of high-dose radiation or ultraviolet light, bacterial infections, and ingestion of harmful chemicals also promote ROS production [4]. The delicate dynamic balance between pro-oxidants (such as ROS) and the antioxidant defense system within the cell constitutes cellular redox homeostasis, which is crucial for normal cellular function, signaling, and survival. At supraphysiological concentrations, ROS react nonspecifically with biomolecules (proteins, lipids, nucleic acids, and carbohydrates), generating other potentially toxic substances. These stimuli activate the cellular antioxidant response system to initiate appropriate countermeasures that maintain homeostasis in the body and prevent this damage from expanding [5]. However, excessive or sustained ROS accumulation disrupts cellular redox homeostasis, causing pathological oxidative stress. Therefore, an imbalance between ROS generation and scavenging contributes to a wide range of degenerative and chronic diseases, including inflammation, cancer, and infectious diseases [6].

In 2007, Yan et al. discovered Fe₃O₄ nanomaterials with peroxidase activity, and a research paradigm for using enzymatic methods to study the biocatalytic properties of nanomaterials was established [7]. These chemically designed nanomaterials with enzyme-like activity, termed “nanozymes”, have attracted extensive research interest for biomedical applications such as drug delivery, biosensing, and antimicrobial and antitumor therapies [8, 9]. Various carbon-, metal-, and metal oxide-nanomaterials have emerged as excellent natural enzyme mimics (Table S1) [10].

Among various nanozyme materials, Pt nanozymes, due to their unique physicochemical properties and ability to mimic multiple key redox enzyme activities, demonstrate significant potential in regulating cellular redox homeostasis and are emerging as a research frontier in this field [11]. This potential is underpinned, in part, by the established biomedical track record of Pt-containing compounds, including antitumor drugs, nerve electrodes and electrical stimulators, and dental implants [12–15]. Significantly, Pt nanozymes exhibit unique capabilities in regulating ROS under pathological oxidative stress due to their partially filled d-orbitals and wide range of accessible oxidation states (Pt⁰, Pt²⁺, and Pt⁴⁺), which enable catalytic reactions via adsorption/desorption process and electronic transfer pathways [16, 17]. In particular, Pt nanozymes hold great potential in regulating ROS in biological processes, exhibiting SOD-like, CAT-like, OXD-like, and POD-like activities without requiring specially designed ligands [18, 19]. Therefore, achieving on-demand, context-dependent “smart switching” between antioxidant and pro-oxidant functions by actively designing or optimizing Pt nanozymes to respond to pathological environmental cues constitutes a key strategy for enabling spatiotemporally controlled redox regulation and precision therapy. Fortunately, this “smart switching” capability of Pt nanozymes can be modulated through external conditions such as nanozyme concentration, H₂O₂ levels, and pH. Under high ROS environments (such as inflammation or ischemia-reperfusion), Pt nanozymes primarily utilize their SOD-like (scavenging O₂^•−), CAT-like (decomposing H₂O₂), and POD-like (scavenging H₂O₂ and organic hydroperoxides) activities to scavenge excess O₂^•− and H₂O₂, thereby exerting antioxidant effects [20–23]. Conversely, in specific microenvironments (e.g., the weakly acidic tumor microenvironment or sites of bacterial infection) or in the presence of specific substrates, their POD-like (converting H₂O₂ to •OH under acidic conditions) and OXD-like activities are activated. This converts relatively mild H₂O₂ or O₂ into highly cytotoxic •OH or other ROS, enabling pro-oxidant effects that eradicate tumor cells or bacteria [24, 25]. Moreover, fine-tuning various physicochemical factors-including size, morphology, composition, surface modifications, and external field energy-enables selective enhancement or suppression of their redox enzyme activities. This optimization enhances their performance under specific conditions (requiring either pro-oxidant or antioxidant functions) and can even confer a degree of stimulus responsiveness. Collectively, this capacity for intelligent functional modulation is propelling Pt nanozymes into an increasingly pivotal role in advanced biomedical applications.

These characteristics exemplify the interdisciplinary integration of Pt nanozymes, which bridge the fields of materials science, chemistry, enzymology, biology, and medicine. Consequently, the concept of utilizing Pt nanozymes to modulate cellular ROS, intervene in the immune response, metabolism, and other ROS-related signaling pathways, and thereby manipulate cellular redox homeostasis has stimulated a global surge in research activity. However, most current studies focus on the single or multiple enzymatic catalytic activities exhibited by Pt nanozymes, often concentrating only on the catalytic function of a certain type of enzyme activity and applying it in catalytic therapy. Simultaneously, the design parameters of Pt nanozymes have not been systematically correlated with their enzymatic performance, resulting in a lack of exploration and systematic elucidation of the “smart switching” mechanism underlying their multi-enzymatic capabilities. Departing from the diverse redox enzymatic properties of Pt nanozymes, this review summarizes a systematic framework encompassing pathological microenvironment responsiveness, enzymatic catalytic mechanism analysis, material design, and disease therapy. It also provides a summary and critical analysis of their clinical translation pathways and current clinical research progress. First, we investigate research trends of Pt nanozymes in biomedical applications through a scientometric perspective, focusing on their pro-oxidant and antioxidant activities. Second, we analyze the possible mechanisms by which Pt nanozymes exert pro-oxidant and antioxidant activities and their “smart switching” capability in response to changes in pathological status and microenvironment during biological processes. Immediately following this, we also discuss strategies to enhance activity and typical applications in biomedicine. Finally, we critically evaluate the limitations and future directions regarding Pt nanozymes preparation, optimization, and ROS regulation for the disease treatment.

Brief bibliometric analysis of the field

This section presents a brief bibliometric analysis focusing on Pt nanozymes for regulating redox homeostasis in organisms. We employed the Science Citation Index Expanded (SCI-EXPANDED), part of the Web of Science Core Collection (WoSCC), recognized for its extensive and inclusive coverage of scientific literature. The specific search criterion employed was as outlined below:

1. Based on the retrieval rules of WoSCC platform and definition of nanozymes, the searching terms were set as: TS (topic subject) = (“Platinum nanozymes*” OR “Platinum nano-enzymes*” OR “Platinum nanoparticle enzyme*” OR “Pt nanozymes*” OR “Pt nano-enzymes*” OR “Pt NPs*”) AND TS = (“Antioxidant*” OR “Pro-oxidant*”) AND TS= (“Oxidative stress*” OR “Redox homeostasis*” OR “Redox regulation*”) AND TS= (“Biomedical*” OR “Nanomedicine*”);

2. The types of included documents were confined to “Articles”;

3. Publications were restricted to those written exclusively in English;

Data extraction for comprehensive scientometric analyses was performed on December 22, 2024, yielding 512 records.

This study included only English-language articles, which may overlook valuable findings in non-English literature; conference papers and reviews were not included, which may affect the comprehensiveness of trend analysis, but this does not impact our main conclusions.

All 512 records were retrieved in the form of tab-delimited text files, containing complete records and cited references. To directly key research topics, the collected 512 records were analyzed using VOSviewer (Version 1.6.20). The obtained 512 records were manually reviewed following the process outlined in Fig. 1c.

Fig. 1.

Bibliometric analysis of the publication in the field of “Platinum Nanozymes in Regulation of Redox Homeostasis in Organisms”. (a) General search process. (b) Co-occurrence network of keywords extracted from the publications. (c) PRISMA flow diagram. (d) Time of occurrence of different keywords, labeled to represent the year in which the keywords are mainly concentrated. (e) Density analysis of different keywords, the brighter the color indicates that the keywords appear more often

Annual publication

Temporal distribution patterns for academic papers within the domain from 2008 to 2024 were detailed in Fig. 2a. The dataset comprised a total of 512 papers. Up to the year 2010, publications on Pt nanozymes in redox homeostasis regulation were sporadic, with fewer than ten papers per year. A modest ascendancy in the rate of annual publications was observed from 2010 to 2016. After 2016, annual publication rates exhibited a rapid and sustained upward trajectory. Thus, the application of Pt nanozymes in the regulation of oxidative stress has garnered increasing attention from researchers over this period.

Fig. 2.

Analysis of publications in the field of “Pt nanozymes and redox homeostasis regulation” and timeline for the development of Pt nanozymes from 1741 to 2024. (a) Annual proportion of total publications from 2008 to 2024. (b) The global distribution of publications in this domain. (c) Timeline for the development of Pt nanozymes from 1741 to 2024

To further understand how publications in different countries evolve from 2008 to 2024, the annual distributions of publications associated with Pt nanozymes are shown in Fig. 2b. The global distribution of publications by country/region is presented in Fig. 2b. A total of 59 countries/regions contributed at least one publication. China dominated the field with the highest number of publications (n = 205, 40.04%), followed by India (n = 58), the USA (n = 49), Japan (n = 45), and South Korea (n = 41). This underscores China’s leading role in this research domain.

In addition to the annual growth and percentage of different countries, Fig. 2c illustrates a historical timeline highlighting key milestones relevant to the development of platinum-based therapeutics and, specifically, Pt nanozymes. The timeline encompasses: (1)”Discovery of Platinum Elements”: the element Pt was first discovered and formally named between 1741 and 1752. (2)”Design of Conventional Platinum Drugs”: the synthesis of cisplatin (1844), the first documentation of its anticancer activity (1965), Marked by FDA approval of cisplatin for testicular cancer (1978), and the subsequent development and clinical use of various platinum drugs (1965–1996), though limited by toxicity. (3) “Design of Multifunctional Platinum Nanozymes”: beginning with the seminal discovery of peroxidase-like activity in Fe₃O₄ nanoparticles (2007) [7], followed by advancements in Pt nanozyme design, such as single-atom catalysis (Pt₁/Fe₃O_X) (2011) [26], and the development of multifunctional Pt nanozymes aimed at enhancing enzyme activity (2011–2018); (4) Current Focus (2018-present): exploiting the antioxidant or pro-oxidant activities of Pt nanozymes to modulate cellular redox homeostasis for disease treatment.

Keyword co-occurrence network analysis

To identify the primary research topics and focus points regarding Pt nanozymes in the regulation of redox homeostasis, we used VOSviewer to extract all keywords from the database (Fig. 1a). After merging synonyms, Fig. 1b shows the co-occurrence network map of 109 keywords, each with a frequency of ten or more. In this map, the size of the labels indicates the frequency of keyword occurrence, whereas the thickness of the lines denotes the strength of the connections between them.

These keywords are organized into four distinct clusters. The analysis of these clusters has revealed a number of topics of particular relevance to Pt nanozymes, including preparation, synthesis, the exertion of antioxidant or pro-oxidant activity, modulation of oxidative stress, and effects on organisms. Within the largest cluster (red), keywords such as “Platinum Nanoparticle”, “Antioxidant”, and “Anticancer” were identified. The yellow cluster contains the cell-related terms “Oxidative Stress”, “DNA Damage”, “ROS”, and “Apoptosis”. The blue cluster contains terms related to cellular metabolites, including “Hydrogen Peroxide”, “Glutathione”, and “Oxygen”. Within the green cluster are terms “Drug Delivery”, “In Vivo”, “Chemotherapy”, and other characteristic terms related to the treatment of diseases. Newer keywords related to ROS, antioxidant activity, and therapy have seen an increase in both frequency and occurrence over time, indicating the growing acceptance of catalytic detection to catalytic therapy among researchers in this field.

It has been observed that the frequency and occurrence of new keywords related to “ROS”, “Oxidative Stress”, “Antioxidant”, “Antitumor”, and “Therapeutic” have increased over time. This increase in the frequency of these keywords suggests a growing focus among researchers in this field on the role of Pt nanozymes as pro-oxidant enzymes or antioxidant enzymes. The purpose of this focus is to modulate the redox homeostasis of cells or organisms, thereby intervening in the treatment of diseases (Fig. 1d, e).

In summary, our bibliometric analysis highlights the burgeoning interest and rapid advancements in Pt nanozymes for regulating redox homeostasis in disease treatment over recent years. The data reveal a significant increase in research output, particularly in the last decade, indicating a growing recognition of the therapeutic potential of Pt nanozymes. Key milestones and the development of innovative nanozyme-based strategies underscore the field’s progress. The keyword co-occurrence and temporal analyses elucidate the current research hotspots and future trends, centered on leveraging the antioxidant or pro-oxidant functions of Pt nanozymes to precisely regulate ROS levels.

Catalytic mechanism of Pt nanozymes for the regulation of ROS

Understanding the catalytic mechanisms by which Pt nanozymes regulate ROS is crucial for their application in redox homeostasis modulation. Maintaining dynamic redox homeostasis is a constant challenge as it involves complex chemical reactions of reactive species derived from oxygen in biological processes [27]. The imbalance between the ROS-generating and scavenging systems can lead to oxidative stress, leading to abnormal cell function and death [28, 29]. The use of nanozymes to regulate the ROS-generating and scavenging is regarded as a feasible strategy. Pt nanozymes can mitigate the adverse effects of oxidative stress by using their antioxidant activity to scavenge overexpressed ROS from metabolic disorders. Conversely, they can combat bacterial infections and tumors by employing pro-oxidant activity to generate ROS. Currently, the catalytic mechanisms of Pt nanozymes mainly involve electron transfer and adsorption/desorption activation. In this section, we classify the four enzymes into two categories based on their catalytic activities and describe the catalytic mechanisms associated with each. As illustrated in Fig. 3a and c, regarding antioxidant activity, the SOD-like activity establishes the initial line of defense against free radicals, converting O₂^•− to H₂O₂ and O₂, followed by H₂O₂ decomposition to H₂O and O₂ catalyzed by CAT/POD-like. For pro-oxidant activity, POD-like and OXD-like activities convert H₂O₂ and O₂ to highly cytotoxic •OH and O₂^•−, respectively (Fig. 3b). We summarize the synergistic effects of different oxidoreductases in disease metabolism.

Fig. 3.

(a) Schematic diagram of Pt nanozymes regulating ROS production and metabolism in disease. (b) Illustration of catalytic reaction mechanisms mediated by Pt nanozymes, including OXD-like, POD-like, SOD-like, and CAT-like. The substrate (Ared) is the chemical substance acted upon by the Pt nanozymes, and the product (Aox) is the molecule resulting from the enzyme-catalyzed reaction. (c) Pt nanozymes exert antioxidant and pro-oxidant activities that synergize with ROS in the regulation of disease. (d) Pathway of H₂O₂ decomposition catalyzed by Pt-NC. (e) Schematic illustration of the catalytic decomposition of H₂O₂ into H₂O and O₂ by Pt-NC. (f) Time-dependent changes in absorbance at 240 nm. (g) Variation in O₂ content within the system. Reproduced with permission from [30]. (h) Changes in superoxide anion levels measured by ESR. Reproduced with permission from [33]. (i) Pathway of H₂O₂ decomposition catalyzed by PtN₄C-SAzyme. (j) UV-Vis spectra showing the oxidation of TMB by H₂O₂ catalyzed by PtN₄C-SAzyme. (k) Changes in •OH levels determined by ESR. Reproduced with permission from [31]. (l) UV-Vis spectra of TMB directly oxidized by Pt@E5. Reproduced with permission from [34]

Antioxidant enzyme

Catalase-like (CAT)

Pt nanozymes are class of nanomaterials with inherent catalase activity that can catalyze the decomposition of H₂O₂ into molecular H₂O and O₂ as shown in Eq. (1):

1

The change of free energy of H₂O₂ decomposition catalyzed by a single active site in Pt was investigated by density functional theory (DFT). Liu et al. proposed the mechanism depicted in Fig. 3d to understand their catalase-like activity [30]. According to this mechanism, the H₂O₂ molecules initially absorb onto the Pt atom (step i), forming the activated state *H₂O₂ (step ii). Subsequently, some evidence suggests that *H₂O₂ molecules preferentially undergo the homolytic reaction, forming two *OH at Pt atoms (step iii, *H₂O₂→2*OH). After that, the *OH reaction produced a surface-adsorbed oxygen atom and an *H₂O molecule (step iv, 2*OH→*O+*H₂O). The introduction of a second H₂O₂ is oxidized to O₂ by *O (step v, *O+H₂O₂→O₂+H₂O). Finally, the desorption of the H₂O molecule leads to the immediate re-exposure of the Pt active site after the generation of O₂, initiating the subsequent cycle (step vi). The reactions on Pt NC were exergonic, indicating they are thermodynamically spontaneous. Furthermore, if *H₂O₂ undergoes heterolytic cleavage to form *OOH and *H (*H₂O₂→*OOH+*H), the results show that the energy of -0.24 eV, a little higher than the corresponding − 0.28 eV of *H₂O₂. Additionally, some in vitro methodologies offer more direct evidence for the ability of Pt nanozymes to catalyze H₂O₂ decomposition and generate O₂ (Fig. 3e). For instance, Fig. 3f demonstrates the decomposition of H₂O₂ by Pt nanozymes by monitoring changes in the characteristic absorption peak of H₂O₂ at 240 nm using UV-Vis spectroscopy. Furthermore, gas chromatography analysis of the O₂ concentration in the system following H₂O₂ decomposition by Pt nanozymes provides additional verification of their CAT-like activity (Fig. 3g). Thus, if H₂O₂ can be decomposed into *OOH and *H, the hetero-cleavage structure will form O₂ and H₂ after optimization. This assertion is evidently unrealistic. Concomitant studies lend further credence to this perspective [31].

Superoxide dismutase-like (SOD)

SOD is an important antioxidant enzyme that catalyzes the conversion of O₂^•− into oxygen and hydrogen peroxide by disproportionation. In this reaction, one O₂^•− anion transfers an electron to the other with the assistance of two protons, generation one H₂O₂ molecule and one O₂ molecule, as shown in Eq. (2):

2

O₂^•− is a Bronsted base with pK_b=9.12. Thus, it will easily capture a proton from system to form HO₂^• and OH⁻ (step i, O₂^•−+H₂O→HO₂^•+ OH⁻); Subsequently, adsorptions of HO₂^• on (111) facets of Pt are facile. The rearrangements for the adsorbed HO₂^• groups are easy (step ii, HO₂^•→HO₂^•*). Thus, HO₂^•* can easily rearrange to give H₂O₂* and O₂* (step iii, 2HO₂^•*→O₂*+H₂O₂*) [19]. Notably, H₂O₂* and O₂* formed in the above processes can undergo further decomposition reactions depending on the types of the Pt facets and the reaction conditions. Some work has shown that (111) facets of Pt have peroxidase-like activities in acidic conditions, H₂O₂* will further decompose to H₂O* and O*. In contrast, H₂O₂ will decompose to H₂O and O₂ in basic conditions, which catalase-like activities in basic conditions [32]. Consequently, the pH of the system is also known to induce changes in enzyme activity. Electron spin resonance (ESR) is a direct and authoritative method for detecting species with unpaired electrons. The superoxide anion inherently possesses paramagnetic properties due to its single unpaired electron. Therefore, Zheng et al. [33] employed ESR to quantitatively monitor changes in superoxide anion levels. Their results demonstrated that upon addition of Pt nanozymes, the ESR signal intensity of the superoxide anion was attenuated, providing evidence for the SOD-like activity of the Pt nanozymes (Fig. 3h).

Pro-oxidant enzyme

Peroxidase-like (POD)

Peroxidases are a class of enzymes that use peroxides (e.g., H₂O₂ or lipid peroxides (ROOH)) to catalyze biological reactions. The peroxides (electron acceptor) are reduced, while the catalyzed substrate (electron donor) is oxidized. The typical reaction catalyzed by a peroxidase can be shown in Eqs. (3) and (4):

3

4

As revealed in Fig. 3i, Yong et al. provide a concise overview of the mechanism: the geometrically optimized H₂O₂ molecule is initially absorbed onto the Pt active centers (step i), forming the absorbed intermediate *H₂O₂ (step ii) [31]. The *H₂O₂ molecule is subsequently cleaved to 2OH* (step iii, *H₂O₂→2*OH). Subsequently, a reactive •OH radical and an adsorbed OH* species are generated upon desorption of one OH* from the single Pt site (step iv). This step has an energy barrier of 0.42 eV, which is easily overcome at room temperature. Finally, desorption of a •OH enables the overall regeneration of the PtN₄C-SAzymes surface for activating another H₂O₂ molecule to generate •OH in the next cycle (step v). It is noteworthy that the •OH generation occurs at the single Pt sites (Pt^δ+) through a homogeneous-like pathway rather than a heterogeneous manner. This phenomenon can be attributed to the relatively low energy barrier associated with homogeneous cracking. Yong et al. [31] evaluated the POD-like activity of Pt nanozymes by catalyzing H₂O₂ to generate •OH, which subsequently oxidizes TMB to produce blue-colored oxidized TMB (oxTMB) (Fig. 3j). Furthermore, ESR was employed to capture the reactive intermediate (•OH) formed during the reaction, providing additional evidence for the POD-like activity (Fig. 3k).

Oxidase-like (OXD)

Pt nanozymes can catalyze the oxidation of organic substrates such as TMB, OPD, MB, 2,2’-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) ABTS, catechol, ascorbic acid (AA), and glucose by O₂ molecules, showing a chemical function similar to oxidases. The typical reaction catalyzed by oxidase can be shown in Eqs. (5) and (6):

5

6

The O₂ in the reaction of Eq. (5) undergoes a two-electron reduction, being reduced to H₂O₂; in the reaction of Eq. (6), the O₂ undergoes a four-electron reduction, being reduced to H₂O. The four-electron reaction can also be regarded as the cascade of reaction Eq. (5) and the peroxidase-like catalysis Eq. (3).

Gao et al. report that dissociative adsorption of O₂ on the metal surfaces to form single-atomic O adatoms is the key step that provides the surfaces with oxidase-like activities [19]. In concrete terms, they studied the mechanism for the four-electron oxidase-like activity of Au, Ag, Pd, and Pt using a DFT systematic study of calculations. Firstly, single-atomic O adatoms on metal surfaces have Bronsted-base character, and they are able to abstract acidic hydrogens from system molecules to act as oxidizing agents. This is because metals pre-covered with O adatoms have demonstrated strong oxidative capability. Subsequently, the ³O₂ molecule first accepts two electrons from Pt to generate the peroxyl (O₂)²⁻ absorbate. Then, the O-O bond dissociated to form the isolated oxygen adatoms. These O-adatoms finally abstracted hydrogen atoms from organic substrates such as TMB to form the products. Because of the chemical inertness of Pt (noble metals), the chemical desorption of O-adatoms by TMB was considered to be facile, and the dissociative chemisorption of O₂ was considered the rate-determining step. For the Pt (111) surface, the activation energy (Eact) for the ¹O₂ dissociations is 0.79 eV, and the reaction energy (Er) is -1.33 eV. These E_act values are lower than those corresponding high-spin ones, indicating that ¹O₂ dissociation is kinetically more facile than that of ³O₂. Furthermore, O₂ molecules can be converted from the high-spin state (³O₂) to the low-spin state (¹O₂) by surface plasmon resonance of metals (such as Pt, Au). Thus, the energy barrier of the dissociation of O₂ could be used to theoretically estimate the oxidase-like activity of this noble metal (Pt) in catalyzing the oxidation of TMB. The results from Zhang et al. [34] demonstrate that Pt nanozymes can directly oxidize TMB in the presence of O₂, thereby exhibiting OXD-like activity (Fig. 3l).

Synergistic and competitive interactions governing the redox plasticity of Pt nanozymes

While the preceding sections delineate the discrete catalytic mechanisms of individual enzyme-like activities, the therapeutic efficacy of Pt nanozymes hinges on the dynamic interplay, competition, and synergy among these multimimetic functions within complex pathophysiological microenvironments. Pt nanozymes do not operate as isolated, single-activity catalysts in vivo; rather, they function as integrated redox nodes whose net output is governed by contextual cues.

The most critical interaction arises from shared substrates and reaction intermediates. For instance, cascades and feedback loops naturally emerge from this interconnected network. The O₂^•⁻ generated by OXD-like activity can be rapidly converted to H₂O₂ by adjacent SOD-like sites. This newly formed H₂O₂ can then be either detoxified (CAT-like) or utilized to fuel further oxidative damage (POD-like), depending on the local conditions. This creates a self-amplifying or self-limiting circuit that allows Pt nanozymes to respond nonlinearly to subtle changes in the redox landscape. Furthermore, H₂O₂ is a nexus molecule, serving as the substrate for both antioxidative (CAT-like decomposition to H₂O and O₂) and pro-oxidative (POD-like conversion to cytotoxic •OH) pathways. The dominance of one pathway over another is exquisitely sensitive to the local microenvironment. Under neutral/alkaline conditions (e.g., in chronic wounds or healthy tissue), CAT-like activity prevails, promoting ROS scavenging and hypoxia alleviation. Conversely, in acidic niches such as the tumor microenvironment (TME) or bacterial infection sites, POD-like activity is markedly enhanced, steering H₂O₂ toward •OH generation and pro-oxidant effects. This pH-gated substrate partitioning is a fundamental mechanism for the observed “smart switching” [35].

Beyond pH, another perspective posits that substrate concentration (e.g., H₂O₂ level) and enzyme concentration are the key determinants driving the activity reversal of Pt nanozymes. For instance, Pompa et al. [18] demonstrated that increasing the concentration of Pt nanozymes promotes the enhancement of pro‑oxidant enzyme activities (OXD‑like and POD‑like), while elevating H₂O₂ concentration boosts both CAT‑like and POD‑like activities, thereby creating a competitive relationship (Fig. 4). However, the specific thresholds at which these competitive interactions trigger a functional switch in Pt nanozymes vary depending on the synthesis method, which dictates parameters such as composition, purity, surface coating, and size. We hypothesize that rational tuning of these parameters beyond a critical threshold could induce a competitive shift, thereby reversing the predominant enzymatic activity of Pt nanozymes.

Fig. 4.

Schematic illustration of the regulation of Pt nanozyme’s OXD-, CAT-like, and POD-like activities. Reproduced with permission from [18]

In summary, the competition for shared substrates (H₂O₂, O₂) and the microenvironment-dependent activation barriers for different pathways collectively enable Pt nanozymes to perform context-aware redox regulation. This sophisticated interplay is not a limitation but a design feature and it underpins the spatiotemporal precision required to scavenge ROS in inflamed tissues while selectively generating lethal ROS in tumors. A deep understanding of these interactions is therefore paramount for rational nanozyme design (including size, morphology, component doping and surface modification), optimization of therapeutic windows, and minimization of off-target effects in future translational applications.

It is of particular importance to analyze the catalytic mechanism of nanozymes through reasonable calculations for further analysis and application. DFT computational studies can predict the electronic structure of the catalysts and the expected reaction paths, whereas from while experimental techniques such as scanning electron microscopy energy spectrometry (EDS), X-ray photoelectron spectroscopy (XPS), nuclear magnetic resonance (NMR), and transmission electron microscopy (TEM) the structure of verify the catalyst structure. More importantly, the development of in situ characterisation techniques enables transient reaction studies of catalytic reactions, including in situ X-ray diffraction (in situ XRD), in situ Raman spectroscopy (in situ Raman), in situ infrared spectroscopy (in situ IR), and other in situ techniques [36]. However, it is of even greater importance to enhance the catalytic activity, substrate specificity, and stability through modulation of the external conditions. This will enable high activity within disease microenvironments, thereby broadening their biomedical applications.

Strategies for tuning catalytic activity of Pt nanozymes

Although a variety of nanozymes have been reported, their practical biomedical applications, including those of Pt nanozymes, often face challenges. The foremost challenge is constructing nanozymes with high and stable catalytic performance within biological environments. To enhance the catalytic activity of Pt nanozymes, several optimization strategies have been proposed, such as size, morphology, composition, and surface modification (Fig. 5).

Fig. 5.

Schematic representation of the effect of size, morphology, composition doping, and surface modification on the enzymatic activity of Pt nanozymes

Size

The regulation of size on the catalytic activity of Pt nanozymes can be considered a double-edged sword. On the one hand, a reduction in size increases the specific surface area of Pt nanozymes and the percentage of surface-exposed atoms. Conversely, a nanozyme size that is too small is prone to agglomeration, which in turn reduces the catalytic activity [37–44]. For example, Shirahata et al. [45] prepared Pt nanozymes of different sizes (1, 2, 3, 3–5 nm) under consistent raw materials and synthesis conditions, and the results showed that smaller-sized (1 nm) Pt nanozymes exhibited stronger ROS scavenging capabilities. Similarly, Wu et al. [46] prepared Pt nanozymes of different sizes (5, 30, 70 nm), and their study also confirmed that smaller-sized Pt nanozymes were more effective in treating colitis. Li et al. prepared Pt/CNTs of varying sizes by regulating the number of cycles of atomic layer deposition. The POD activity initially increased and then decreased as the Pt/CNT size decreased (Fig. 6a, b) [43]. The Pt/CNTs with a diameter of 1.69 nm exhibited the most pronounced POD activity, suggesting that smaller Pt/CNTs are more active, require less material, and are less costly when presenting the same number of catalytically active sites. Huang et al. discovered that adjusting the diameters of Pt NWs can alter the activity and durability of the oxygen reduction reaction (ORR) (Fig. 6c, d) [44]. Wang et al. fabricated Pt/Ga₂O₃ heterojunctions with different sized Pt (1.5 to 2.7 nm) were fabricated through the photodeposition method and used for nonoxidative photocatalytic CH₄ conversion under mind conditions (Fig. 6f) [39]. The smaller size is beneficial to the formation of Pt^δ+ species and promotes C-H activation (Fig. 6e). Han et al. used different-sized MXene-Pt nanozymes for lactate analysis [42]. The uniform distribution of small-sized Pt NPs gives rise to superior electron transfer kinetics, thereby maximizing lactic acid detection capabilities. It can therefore be concluded that the rational use of the size effect to regulate the parameters, such as the number of surface-exposed atoms and the specific surface area of nanozymes, can effectively improve the catalytic performance. While reducing size enhances specific surface area and catalytic efficiency, it introduces significant trade-offs. Aggregation becomes more pronounced for ultrasmall Pt nanoparticles due to high surface energy, which can drastically reduce accessible active sites and mimic low activity. Standardized characterization is crucial: dynamic light scattering (DLS) may overestimate size due to aggregation, while TEM provides number-average size but not distribution in physiological media. Activity comparisons across studies are often confounded by normalization discrepancies (e.g., activity per mass vs. per surface atom vs. per particle). Furthermore, extremely small nanoparticles may exhibit quantum size effects with unpredictable catalytic behavior and altered redox potentials. Recommended controls: (i) Reporting multiple size characterization methods (TEM, HAADF-STEM, DLS in relevant buffers). (ii) Assessing colloidal stability over time under biologically relevant conditions (e.g., in PBS, cell culture media). (iii) Clearly stating the basis for catalytic activity normalization to enable meaningful cross-study comparison.

Fig. 6.

The effect of size on catalytic reactions. (a) Illustration of the preparation process of Pt/CNTs nanozymes. (b) TEM images of Pt/CNTs nanozymes. Reproduced with permission from [43]. (c) Nature of size effect: the competition between strain and coordination number (CN) effect. (d) HAADF-STEM images of Pt NWs-1.1/1.5/2.4. Reproduced with permission from [44]. (e) The effect of size of Pt NPs on the photocatalytic nonoxidative coupling of methane. (f) HRTEM images of Pt/Ca₂O₃-1.5/1.9/2.2/2.5/2.7. Reproduced with permission from [39]

Morphology

The fundamental principle of morphology modulation is the regulation of the number of active sites that are exposed on the crystal surface [47]. In general, porous and dendritic structures with a high specific surface area will have a greater number of active sites [48]. For example, porous Pd-Pt has been observed to exhibit stronger POD activity in comparison to Pd-Pt nanorods [49]. Ge et al. have demonstrated that Pd-Pt nanocrystals display enhanced antimicrobial activity when converted to Pt hollow nanodendrites through the selective removal of the Pd cores (Fig. 7a) [50]. Xu et al. have synthesised flower-like (FPDA@Pt) and mesoporous spherical (MPDA@Pt) nanozymes (Fig. 7b, c) [51]. Among these, the flower-like FPDA@Pt exhibited superior POD activity and photothermal conversion efficiency. Sun et al. synthesized Pt-Ni NPs with three different crystalline surfaces (Fig. 7d, e, f) [52]. The results demonstrated that the high-index crystalline surfaces were more conducive to the activation of reactive species. Consistent with this trend, CuPt_2.22 NWs with higher-index surface structures exhibit stronger activities than CuPt_1.78 NTs [53]. Chen et al. extended the dimensionality from one-dimensional to three-dimensional structures by synthesizing PtNi₃ nanoframes [54]. In comparison to alternative materials, the framework structure is more open and thus capable of exposing a greater number of active sites. Complex morphologies (e.g., dendrites, nanoframes, high-index facets) often require intricate, multi-step syntheses that pose challenges for batch-to-batch reproducibility and scale-up. The precise control over exposed crystal facets can be sensitive to subtle variations in precursor ratios, temperature, and capping agents. Moreover, the relationship between morphology and activity is not always generalizable; optimal morphology for one enzyme-mimic activity (e.g., POD-like) may differ for another (e.g., CAT-like). Aggregation of anisotropic structures (e.g., nanowires, nanosheets) can be severe, masking their theoretical high surface area advantage. Characterization artifacts in electron microscopy, such as preferential orientation on grids, can lead to misrepresentation of the true 3D morphology distribution. Recommended controls: (i) Providing detailed, reproducible synthesis protocols with error margins for key parameters. (ii) Using statistical analysis from large-field TEM/SEM images to report morphological yield and uniformity. (iii) Correlating morphology with multiple enzymatic activities to establish structure-function relationships rather than focusing on a single metric.

Fig. 7.

Pt nanozymes with various morphologies. (a) TEM images of Pt Hollow Nanodendrites. Reproduced with permission from [50]. (b, c): TEM images of FPDA@Pt and MPDA@Pt. Reproduced with permission from [51]. (d, e, f) TEM images of concave nanocubes Pt-Ni NPs、nanocubes Pt-Ni NPs and hexoctahedra Pt-Ni NPs. Reproduced with permission from [52]

Component doping

The introduction of additional components during the synthesis of nanozymes typically results in a change to their original single electronic structure, which in turn affects their catalytic activity [55]. Zheng et al. combined Pt nanozymes with Co monoatoms, exploiting the overlap of electronic orbitals between Pt and Co to enhance electron transfer between the two, improve the adsorption of free radicals, and reduce the reaction energy (Fig. 8a, b, c) [56]. This approach led to an improvement in the SOD-like and CAT-like activities of the Pt nanozymes. Cheng et al. discovered that the combination of Pt NPs and Ni(OH)₂ nanosheets resulted in an increase in binding energy for the adsorption of reaction intermediates, thereby enhancing POD-like activity [57]. Song et al. reported that depositing Ir on dendrimer-structured Pd-Pt enhanced POD-like activity [58]. Wu et al. enhanced POD-like activity by doping Pd nanoparticles with Pt to construct Pd@Pt NPs, which exhibited enhanced activity over natural horseradish peroxidase [59].

Fig. 8.

The effect of compositional doping on reaction activity. (a) TEM and HAADF-STEM images of the Co-SA-NSG. (b) TEM and HAADF-STEM images of the Pt/Co-SA-NSG. (c) Corresponding calculated adsorption energies. Reproduced with permission from [56]. (d) HRTEM images of the US-HEANPs. (e) The optimized structures of H₂O₂ and •OH adsorbed on US-HEANPs at different sites. Reproduced with permission from [63]. (f) HAADF-STEM images of Ni-Pt NPs. (g) DFT calculations. Reproduced with permission from [64]

Forming hybrid complexes is another effective strategy. For example, Sun et al. prepared Pt₄₈Pd₅₂-Fe₃O₄ hybrid materials, which exhibited augmented POD-like activity in comparison to PtPd NPs and Fe₃O₄ NPs alone [60]. Fan et al. discovered that when Au/Pt was doped at a ratio of 1:1, AuPt NPs exhibited the highest glucose oxidase activity, which could be attributed to electronic coupling or strain effects [61].

Alloying represents a powerful approach to retune the electron distribution and geometry of nanozymes, thereby achieving excellent catalytic performance. Wang et al. prepared a series of porous Pt/Ag nanoparticles via a simple and economical alloying process [62]. Among them, the D-Pt₅₀Ag₅₀ nanoparticles exhibited a bimetallic synergistic effect with good inhibition against Escherichia coli and Staphylococcus aureus. The ultra-small-sized high-entropy alloy PtPdRuRhIr US-HEANPs also demonstrated excellent POD-like activity (Fig. 8d, e) [63].

Furthermore, adjusting the ratio of components is another key strategy to enhance nanozyme activity. Xia et al. conducted a variation in the Ni and Pt doping ratios during the synthesis process, resulting in the production of a series of Ni-Pt₂ NPs, Ni-Pt NPs, and Ni-Pt_0.5 NPs [64]. Among these, the Ni-Pt NPs exhibited the highest Kcat value. Subsequent DFT calculations demonstrated that the least favorable HO*/O* adsorption on the surface of Ni-Pt NPs was conducive to enhancing POD-like activity (Fig. 8f, g). Doping or alloying introduces complexity in structural and chemical homogeneity. Inhomogeneous distribution of dopants or phase segregation in alloys can create a mixture of active sites with varying activities, making mechanistic interpretation difficult. The synergistic effect is often claimed but requires careful deconvolution from simple additive effects of individual components. Surface depletion or enrichment of a specific element (surface segregation) can occur, meaning the bulk composition does not reflect the catalytically relevant surface composition. Electronic structure modulation via doping, while powerful, is highly sensitive to the local atomic arrangement and coordination number, which are challenging to characterize precisely and reproduce consistently. Recommended controls: (i) Employing elemental mapping (EDS/STEM) and surface-sensitive techniques (XPS) to verify dopant distribution and surface composition. (ii) Comparing the doped nanozyme’s activity not only to individual components but also to physical mixtures of them. (iii) Using theoretical calculations (DFT) in tandem with experimental data to rationalize the observed synergy. In summary, doping specific components or altering their ratios in Pt nanozymes can effectively tune their enzymatic activity.

Surface modification

The high surface energy of nanozymes renders them susceptible to the influence of other ions present in the system, which can lead to agglomeration and subsequent impairment of their activity. Consequently, the appropriate surface ligand modification of Pt nanozymes not only improves the stability of the entire system but also enhances the biocompatibility and targeting of Pt nanozymes.

Ma et al. prepared well-dispersed cubic Pt nanozymes using cetyltrimethylammonium bromide (CTAB) as a surface stabilizer for Pt nanozymes, which effectively avoided the clustering phenomenon and improved the activity of the POD-like San et al. coated Pt nanozymes with PepA, DegP and ClpP proteins, respectively, which demonstrated enhanced stability and SOD activity [65]. Guo et al. observed that Pt²⁺ on the surface underwent reduction to Pt⁰ upon binding of S²⁻ to CM-PtNP, thereby improving stability and activity [66]. Fan et al. achieved tumor targeting by covering porous Pt nanoparticles with a mimetic dopamine (PDA) and subsequently coupling Z_EGFR with pPt@PDA nanoparticles (Fig. 9a, b) [67]. The modification of Pt nanozymes with betaine has been demonstrated to enhance biocompatibility and tumor targeting, with an anti-tumor effect of 96.48% [68].

Fig. 9.

The effect of surface modification on reaction activity. (a) Schematic illustration of the process of Z_EGFR conjugation to pPt@PDA NPs. (b) HAADF-STEM images of pPt and pPt@PDA NPs. Reproduced with permission from [67]. (c) PEG in biomedical applications. Reproduced with permission from [71]. (d) TEM image of mPt NPs and Pt@PEG-Ce6. Reproduced with permission from [74]. (e) Schematic illustration of the employed PEG to bridge Au₂Pt and Ce6. (f) CT images of Au₂Pt-PEG-Ce6 NPs. Reproduced with permission from [75]

Polyethylene glycol (PEG) has been employed extensively to enhance the water solubility, stability, and prolong the half-life of hydrophobic nanozymes. Furthermore, it can facilitate the linkage of additional substances, thereby enhancing the multifunctionalities of nanozyme surface properties, reducing immunogenicity, and optimizing pharmacokinetic behavior in vivo. This, in turn, enhances the value of its application in the clinic (Fig. 9c) [69–71]. Yang et al. enhanced the biocompatibility and tumor-targeting capabilities of Cu-Pt(IV) NPs by modifying PEG [72]. Similarly, Yang et al. PEGylated Au-Pt NPs, which enhanced the uptake of Au-Pt NPs by tumors, thereby improving the energy deposition of X-rays at tumors [73]. Lu et al. employed chloroplatinic acid as a precursor and constructed Pt@PEG-Ce6 by modifying PEG-Ce6 onto mPt using SH-PEG-NH₂ (Fig. 9d) [74]. Subsequent cell and animal experiments demonstrated that Pt@PEG-Ce6 nanoprobes were capable of decomposing H₂O₂ in tumors to produce O₂, thereby overcoming the state of anoxia in the tumor system. Additionally, Ce6 induced the generation of ROS from O₂ to destroy the tumors under light exposure. Wang et al. employed PEG to bridge Au₂Pt and Ce6, resulting in the construction of Au₂Pt-PEG-Ce6 (Fig. 9e) [75]. This approach enabled the achievement of synergistic anti-tumor therapy with phototherapy and chemotherapy. Furthermore, the distinctive physical characteristics of Pt enabled the development of Au₂Pt-PEG-Ce6, which could be imaged using computed tomography (CT) (Fig. 9f). Chen et al. employed a palladium-platinum bimetallic enzyme (PP) as a carrier, successfully establishing a covalent bond between ART and PP through the introduction of ester bonds via PEGylation [76]. ART was catalyzed by endogenous Fe²⁺ to generate O₂^{• -}, which combined with PP to catalytically produce •OH, thereby achieving a synergistic anti-tumor effect. Surface modification, essential for stability and targeting, can inadvertently passivate active sites and reduce intrinsic catalytic activity. The formation of a dense protein corona in biological fluids can further alter the surface properties, enzymatic activity, and cellular targeting efficiency, leading to discrepancies between in vitro and in vivo performance. Ligand exchange or desorption in complex media is a common instability issue. While PEGylation improves pharmacokinetics, it can induce accelerated blood clearance (ABC phenomenon) upon repeated administration and may hinder cellular uptake. The choice of modifier (e.g., charge, hydrophilicity) must balance between preventing non-specific adsorption and maintaining the desired bio-interaction. Recommended controls: (i) Measuring enzymatic activity before and after surface coating under identical conditions. (ii) Characterizing the hydrodynamic size, zeta potential, and activity after incubation in biological media (e.g., serum) to assess corona effects. (iii) Evaluating targeting efficiency in relevant cellular models with and without competitive inhibitors to confirm receptor-specificity.

Other strategies

The composition and structure of nanozymes are fundamental determinants of their catalytic properties. The four aspects of size, morphology modulation, component doping, and surface modification interact with each other to alter the number of active sites in contact with the substrate, thereby modulating the catalytic efficiency of the nanozymes. Furthermore, the distinctive physicochemical characteristics of Pt nanozymes are susceptible to influence from additional environmental factors, including the pH of the solution and the energy of the external field.

Fan et al. demonstrated that the catalytic activities of Pt-Ft NPs are influenced by changes in temperature and pH within the system [77]. The authors observed that CAT-like activity was exhibited in neutral/alkaline conditions, while POD-like activity was observed in acidic conditions. Liu et al. found that Pt nanozymes have strong O₂^•− scavenging ability in neutral or weakly alkaline conditions, but low activity in acidic conditions [78]. Additionally, the highly ordered PtCu₃ structure possesses acoustic sensitizer properties and enhances both POD/GPx-like activities under ultrasound radiation [79]. In a separate experiment, the T790 acoustic sensitiser was loaded onto the surface of the Pd₂@Pt NPs. It was observed that the loading of T790 resulted in a notable attenuation of the CAT-like activity of Pd₂@Pt [80]. However, the addition of ultrasound stimulation led to the restoration of CAT-like activity.

The aforementioned diversified designs are intended to enhance the activity of Pt nanozymes. However, as the adage “too much water drowns the miller” illustrates, redundant and superfluous modifications not only fail to enhance the material’s activity but also increase the cost of preparation. It can therefore be seen that the activity of Pt nanozymes is strongly influenced by their characteristics and the environmental system in which they are embedded. This makes the so-called “universal” strategy difficult to implement. In conclusion, to rationally design Pt nanozymes, it is necessary to adopt more advanced and environmentally friendly synthesis methods and to achieve a balance between the desired catalytic performance, the structure of the nanozymes, and the cost. Future efforts should focus on synthesizing Pt nanozymes that exhibit high biocompatibility, uniform morphology and size, high stability, and excellent catalytic performance. Achieving this requires careful consideration of the complexity and variability of biological systems.

Biomedical applications of Pt nanozymes

Pathological diseases are frequently accompanied by an imbalance in ROS within the organism. While chemical pharmaceuticals can intervene and treat these conditions, they often entail unpredictable side effects such as high immunogenicity and allergic reactions (detailed examples are provided in Sect. 5.1.2). Fortunately, pathological diseases can also be treated by modulating ROS levels through enzymatic catalysis. Examples include alteplase for cardiac diseases and velaglucerase alfa for Gaucher’s disease [4, 81]. Although these natural enzymes exhibit therapeutic efficacy, issues such as susceptibility to degradation, short half-life, and lack of target specificity often prevent them from reaching effective concentrations at the intended sites in vivo. Consequently, despite the vast diversity of natural enzymes, only a limited number have been successfully developed into drugs. In contrast, most nanozymes possess redox regulatory functions. Notably, Pt nanozymes, which can effectively catalyze either the generation or scavenging of ROS, have been employed in treating a variety of diseases. For instance, antioxidant Pt nanozymes primarily function by scavenging ROS, thereby delaying aging processes, repairing tissues, and alleviating inflammation (Table 1). Conversely, pro-oxidant Pt nanozymes exert therapeutic effects by generating ROS for applications in antitumor and antibacterial therapies (Tables 2 and 3). Significantly, several Pt nanozyme-based formulations have already been approved for clinical use or are currently under clinical investigation (Table S2). Section 5 primarily discusses the characteristics of different diseases and the mechanisms by which Pt nanozyme-based therapies treat them, as illustrated in Fig. 10.

Table 1.

Pt nanozymes with antioxidant activity scavenge ROS via SOD/CAT/POD-like cascade catalysis for tissue repair and inflammation alleviation

Nanozymes	Size/nm	Element	Enzyme-like activities	External energy	Administration route	Concentration	Half-life (t1/2)/h	Applications	Ref
Au-Pt nanocomposites	50	Au; Pt	SOD; CAT	/	/	/	/	Antioxidant	[87]
Pt NPs	2	Pt	SOD	/	/	50 µg/mL	/	Antioxidant	[45]
PtPdRh Nanocubes	10.2 ± 0.7	Pt; Pb; Rh	SOD; CAT; POD	/	Intraperitoneal injection	V = 200 µL C = 5 mg/mL	/	Radiotherapy Protection	[85]
PtPd Nanocubes	23.53 ± 2.09	Pt; Pb	SOD; CAT;	/	Intraperitoneal injection	V = 200 µL C = 5 mg/mL	/	Radiotherapy Protection	[84]
Pt NPs	5	Pt	SOD; CAT; POD	/	Topical application	C = 1 mg	/	Antilight Aging	[20]
Pt@PCN222-Mn	200	Pt; Mn	SOD; CAT	/	Intraperitoneal injection	C = 0.5 mg/kg	/	IBD	[96]
Pt/Co-SA-NSG	2.7	Pt; Co; N; S	SOD; CAT	NIR II	Intraperitoneal injection	C = 8 µg/mL	/	OA	[56]
Pt NPs	/	Pt	SOD; POD	/	/	C = 300 µM	/	Antioxidant	[97]
CeO2@Pt	80	Pt; Ce; O	SOD; CAT	/	Intraperitoneal injection	C = 0.5 mg/kg	/	IBD/Ear Inflammation	[100]
Pt NPs	5/30/70	Pt	POD	/	Oral administration	C = 2.8 µg/mL	/	UC	[46]
Pt NCs	2	Pt	POD	/	Oral administration	V = 100 µL C = 1 mg/mL	/	IBD	[103]
PtCD@NP	190.14	Pt; C; O	SOD; CAT	/	Intravenous injection	C = 5 mg/kg	0.84 h/2.03 ± 0.92	UC	[107]
PtsaN-C	5–10	Pt; N; C	SOD; CAT; POD	/	In situ injection	V = 10 µL C = 500 µg/mL	/	I/R Injury	[23]
PbPt@MnO2	54.23	Pt; Pb; Mn	SOD; CAT; POD	/	Intravenous injection	C = 1.25/2.5/5 mg/kg	/	LI	[109]
Pt@CNDs	3.2 ± 0.5	Pt; C	SOD; CAT	/	Intravenous injection	C = 1.5/2.5/4 mg/kg	0.8	LI/Ear Inflammation	[110]
Pt-iNOS@ZIF	≈ 100	Pt; Zn; C; N	SOD; CAT	/	Intravenous injection	C = 2 mg/kg	/	Hepatic IRI	[21]
Pt NPs	30/106	Pt	SOD; CAT	/	Intravenous injection	C = 50 µg/kg	/	Hepatic Ischemia/Reperfusion Injury	[112]
Ag@Pt-NIL/HA Nanotriangles	60–70	Pt; Ag	SOD; CAT	/	Intravenous injection	C = 10 mg/kg	/	Liver Fibrosis	[114]
Pt NZs	≈ 6.8	Pt	SOD; CAT	NIR I	In situ injection	C = 300 µg/mL	/	Liver Fibrosis	[115]
PtCuOX/CeO2−X	≈ 170	Pt; Cu; Ce; O	SOD; CAT	NIR I	Intra-articular injection	V = 100 µL C = 50 µg/mL	/	OA	[123]
Pt@PCN222-Mn	≈ 200	Pt; Mn	SOD; CAT	/	In situ injection	V = 30 µL C = 40 µg/mL	/	TMJ OA	[124]
Pt@ZIF-8@La	≈ 100	Pt; La	SOD; CAT	/	In situ injection	C = 10 mg/kg	/	Aseptic Osteolysis	[121]
Pt SA/C3N4	/	Pt	SOD; CAT	NIR I	Intra-articular injection	V = 100 µL C = 0.05 mg/mL	/	OA	[17]
Pt/Co-SA-NSG	/	Pt; Co	SOD; CAT	NIR II	Intra-articular injection	V = 200 µL C = 8 µg/mL	/	OA	[56]
HMPB-Pt@MM	≈ 181.77	Pt; Mn	SOD; CAT; UOD	/	Intra-articular injection	C = 8 mg/kg	/	GA	[136]
ARP-PtNCs	≈ 3	Pt	SOD; CAT; POD; UOD	/	/	/	/	Gout/ Hyperuricemia	[137]
Pt/CeO2	/	Pt/Ce	CAT; UOD	/	Intra-articular injection	V = 50 µL	/	Acute Gout	[138]
D-N[EM2]	/	Pt	CAT	NIR I	Topical application	/	/	Gouty Arthritis	[22]
BSA-BR-Pt NPs	395.9 ± 52.3	Pt	CAT	/	Intra-articular injection	/	/	RA	[144]
Janus-CPS	≈ 100	Pt; Ce	SOD; CAT	NIR II	Intravenous injection	V = 100 µL C = 2 mg/mL	/	RA	[145]
Pt NPs	≈ 5	Pt	SOD; CAT; POD	/	In situ injection	V = 1 µL C = 0.3/1 µM	/	LIRD	[150]
Pt NPs	4	Pt	CAT	/	In situ injection	V = 2 µL	/	AMD	[146]
Pt@MitoLipo	≈ 50	Pt	SOD; CAT	/	In situ injection	V = 1 µL m = 0.5/1 µg	/	Retina Neovascularization	[151]
DTPNCs	160	Pt	SOD; CAT; POD	/	In situ injection	V = 25 µL C = 3 mg/mL	/	Diabetic Cataract	[149]
Pt NPs-PVP	4.5	Pt	CAT; POD	/	Intravenous injection	V = 150 µL m = 500 µg	/	AKI	[156]
MM-PtNCs	88.5 ± 3.2	Pt	CAT	/	Intravenous injection	C = 15 mg/kg	/	AKI	[155]
Pt5.65S	14.45 ± 2.613	Pt; S; C	SOD; CAT	/	Intravenous injection	C = 15 mg/kg	/	AKI	[153]
RuPt Nanozyme	5–20	Pt; Ru	SOD; CAT	/	Intravenous injection	/	/	AKI	[157]
Pt/HK-NMs	20	Pt	CAT	/	Intraperitoneal injection	C = 1.5 µg/g	/	AKI	[158]
AuPt NPs	166.2 ± 2.5	Pt; Au	CAT; POD	/	Intravenous injection	V = 150 µL m = 1.5 mg	8.574 ± 0.144	Kidney IRI	[159]
Pt NWs	≈ 3.1	Pt	SOD; CAT; GPx	/	Topical application	m = 50 µg	/	Psoriasis/Rosacea	[162]
Pt-CDs	2–3	Pt; C	CAT	/	Topical application	m = 0.25 mg/cm2	/	Psoriasis	[161]
PAPLAL	/	Pt; Pb	SOD; CAT	/	Topical application	0.2 mg/mL	/	Skin Atrophy	[165]
PtCuSe	/	Pt; Cu; Se	SOD; CAT	/	Intravenous injection	m = 8 mg/kg	/	PD	[171]
Pt/CeO2	≈ 222.47	Pt; Ce; O	SOD; CAT; POD; GPx	/	Intravenous injection	C = 50 µg/mL	/	PD	[172]
Ptzyme@D-ZIF	70.37 ± 15.84	Pt; Zn; C; O; N	SOD; CAT	/	Intravenous injection	C = 5 mg/kg	6.72	PD	[175]
PtCu NAs	32.1 ± 4.5	Pt; Cu	SOD; CAT; POD	/	Stereotactic injection	V = 2 µL m = 0.35 µg	/	PD	[177]

Table 2.

Pt nanozymes with pro-oxidant activity generate ROS via OXD/POD-like cascade catalysis for antitumor applications

Nanozymes	Size/nm	Element	Drug loading	Enzyme-like activities	External energy	Administration route	Concentration	Half-life (t1/2)/h	Applications	Ref
DPC@Pt@M	542.85 ± 56.96	Pt; Se	PTX; Ce6	SOD; CAT; POD	US	Intravenous injection	/	2.78	Colon Cancer	[184]
Pt-nano	≈ 1	Pt	/	SOD; CAT	/	In situ injection	C = 1.54 µmol/kg (40.3 mg/kg)	/	Antitumor	[187]
Pt@PEG-Ce6	164	Pt	Ce6	CAT	NIR I	Intravenous injection	V = 100 µL C = 1 mg/mL	/	Breast Cancer	[74]
Pd@Pt-PEG-Ce6	≈ 80	Pt; Pb	Ce6	CAT	NIR I	Intravenous injection	V = 200 µL C = 1 mg/mL	≈ 2	Breast Cancer	[189]
PCN-224-Pt	≈ 90	Pt; Zn	MOFs	CAT	/	In situ injection Intravenous injection	V = 200 µL C=2 mg/mL V = 500 µL C=1 mg/mL	/	Antitumor	[191]
ICPA	≈ 200	Pt	ICG	CAT	NIR I	Intravenous injection	V = 50 µL C = 5 mg/mL	/	Antitumor	[190]
nano-Pt/VP@MLipo	120	Pt	Verteporfin	CAT	NIR I	Intravenous injection	V = 50 µL C=5 mg/kg	12.3	Breast Cancer	[193]
CDs@Pt SAs/NCs@DOX	95.0 ± 5.0	Pt; C	DOX	POD; GPx	NIR I	Intravenous injection	V = 100 µL C = 2.255 mg/mL	3.9	Breast Cancer	[197]
Ti3C2Tx-Pt-PEG	≈ 200	Pt; Ti	/	POD	NIR II	Intravenous injection	/	/	Breast Cancer	[206]
PtPB	≈ 110	Pt; Mn	PB	SOD; CAT	NIR I/NIR II	Intravenous injection	V = 200 µL C = 1 mg/mL	/	Breast Cancer	[208]
PNP	≈ 200	Pt	/	CAT	NIR I		V = 200 µL C = 1 mg/mL	/	Breast Cancer	[209]
TOh Au@Pt-PEG-Ce6/HA	≈ 200	Pt; Au	Ce6	CAT	NIR I	Intravenous injection	C = 10 mg/kg	/	Antitumor	[217]
APIJNS	≈ 220	Pt; Au	ICG	CAT; POD	NIR I	Intravenous injection	/	/	Antitumor	[219]
CP1-NC	≈ 78	Pt	/	/	NIR I	/	/	/	Antitumor	[221]
Zn/Pt SATs	≈ 100	Pt; Zn; Ti; O	/	CAT; POD	US	Intravenous injection	V = 200 µL C = 20 mg/kg	/	Breast Cancer	[234]
BiF3@BiOI@Pt-PVP	70 ± 20	Pt; Bi; I; F; O	/	CAT	US	Intravenous injection	/	/	Breast Cancer	[235]
TiO2@Pt/GOx	≈ 133	Pt; Ti	GOx	CAT	US	Intravenous injection	C = 40 mg/kg	2.96	Breast Cancer	[238]
PtPdRuRhIr US-HEANPs	≈ 1.5	Pt; Pd; Ru; Rh; Ir	/	POD	NIR I	Intravenous injection	V = 50 µL C = 1 mg/mL	/	Antitumor	[63]
HCS@Pt-Ce6 NPs	110	Pt; C	Ce6	POD; OXD; GPx	NIR I	Intravenous injection	C = 7.5 mg/kg	8.34	Antitumor	[244]
NMPNs	2.5	Pt	/	POD; OXD	/	Intravenous injection	C = 2.5 mg/kg	/	Antitumor	[245]
PtFe@Fe3O4	5–20	Pt; Fe; O	/	CAT; POD	NIR I	Intravenous injection	C = 20 mg/kg	/	Pancreatic Cancer	[246]
ACPP	9.5	Pt; Au; Cu	/	GOD; SOD; CAT; POD; GPx	US	Intravenous injection	C = 2 mg/mL	4.02	Breast Cancer	[252]
PTX-SS-HPPH/Pt@RGD-NP	164.9 ± 1.4	Pt	PTX; HPPH	CAT	NIR I	Intravenous injection	C = 0.747 mg/kg	/	Bladder Cancer	[258]
PtPd Nanozymes	153	Pt; Pb	/	OXD; CAT; POD; GPx	/	Intravenous injection	C = 75 mg/kg	/	Breast Cancer	[265]
Pt/Ce6-LP	128 ± 11	Pt	Ce6	/	NIR I	Intravenous injection	C = 0.2 mg/kg	0.51 ± 0.15	Antitumor	[266]
CLP@HP-A	330	Pt	Ce6; Lenvatinib	SOD; CAT; POD	US	Intravenous injection	C=10 mg/kg	1.413	Thyroid Cancer	[240]
DMSNs	≈ 200	Pt; C	/	POD; CAT	NIR I	Intravenous injection	V = 20 µL C=2 mg/mL	/	Antitumor	[280]
CCP@HP@M	200	Pt	Ce6; Chloroquine	SOD; CAT	US	Intravenous injection	C = 10 mg/kg	1.46 ± 0.29	Colorectal Cancer	[241]
fd-AR-TN@PtNE Nanofibers	1300	Pt	ICG	CAT	NIR I	Intravenous injection	V = 100 µL C = 200 µg/mL	/	Breast Cancer	[281]

Table 3.

Pt nanozymes with pro-oxidant activity generate ROS via OXD-POD-like cascade catalysis for antibacterial applications

Nanozymes	Size/nm	Element	Enzyme-like activities	External energy	Administration route	Concentration	H2O2	Applications	Ref
Pt Hollow Nanodendrites	18	Pt; Pb	POD	/	Subcutaneous injection	C = 1.25 × 10− 4 M	1 × 10− 3 M	Anti-E. coli and S.aureus	[50]
AuPt NDs	2.5	Pt; Au	POD	NIR I	Subcutaneous injection	V = 100 µL	0.5 mM	Anti-E. coli and S.aureus	[291]
Pt@Si	267.8	Pt; Si	POD	NIR I	Subcutaneous injection	C = 200 µg/mL	/	Anti-S.aureus	[285]
PtAu Nanozymes	1.98 ± 0.41	Pt; Au	POD; OXD; NOx	/	Subcutaneous injection	C=1 mg/kg	/	Anti-E. coli and S.aureus	[290]
BiPt@HMVs	72.96	Pt; Bi	POD; OXD	US	Intravenous injection	C=10 mg/kg	/	Anti-E. coli and MRSA	[292]
PtRu/C3N5	141	Pt; Ru	OXD	US	Subcutaneous injection	/	/	Anti-S. aureus, MRSA, E. coli, and P. aeruginosa	[302]
Pt-Ti3C2	/	Pt; Ti; C	POD	NIR I	Subcutaneous injection	C = 40 µg/mL	0.1 mM	Anti-S.aureus	[301]
CuS@Pt-Au/Apt NPs	180	Pt; Cu; S; Au	POD; OXD; GOD	NIR I	Subcutaneous injection	V = 200 µL C=2 mg/mL	/	Anti-S.aureus	[303]
PFOB@PLGA@Pt	2–4	Pt	POD; OXD; CAT; SOD	/	Topical application	V=1mL	/	Anti-S.aureus	[308]
GOx-CaPCuPt	260 ± 15	Pt; Ca; P; Cu	POD; OXD; CAT	NIR I	Topical application	V = 200 µL C = 200 µg/mL	/	Anti-S.aureus	[306]
APGH	≈ 100	Pt	POD	/	Topical application	V = 300 µL C=2 mg/mL	/	Anti-S. aureus	[304]
Pt-Fmoc-FF	5.3	Pt	POD; OXD	/	/	/	10 µmol/L	Anti-E. coli and S. aureus	[305]
PtCuTe	148	Pt; Cu; Te	POD	/	Topical application	C = 5 µg/mL	/	Anti-S.aureus	[311]
PPCN@Pt-AMPs/HGel	≈ 100	Pt	CAT	US	Topical application	C = 1 mg/mL	/	Anti-E. coli and MRSA	[312]

Fig. 10.

Engineered Pt nanozymes with enhanced enzymatic activity through general strategies for biomedical applications

Pt nanozymes with antioxidant activity

Radiation-induced damage

Exposure to X-rays or large doses of UV radiation rapidly generates a large amount of ROS, which disrupts the redox homeostasis of cells and causes oxidative damage in multiple organs and tissues [4]. While amifostine has been approved as a radioprotective agent for a long time, the short elimination half-life and systemic toxicity greatly limit its radioprotective efficacy [82, 83]. Pt nanozymes have multiple antioxidant (CAT/SOD-like) activity and can scavenge radiation-induced ROS (O₂^•− and H₂O₂) [20, 45, 84–88]. For example, as early as 2008, Hamasaki et al. found that ultrasmall Pt nanoparticles could scavenge •OH and O₂^•−, which significantly protected HeLa cells from ROS damage-induced cell death [45]. Furthermore, Xu et al. had suggested that ultrasmall Pt clusters could not only recover the bone marrow DNA level and SOD-like activities via scavenging ROS, but also improve the survival rate of irradiated mice up to 30% [88]. Zhang et al. explored the protective effects of bimetal nanozymes, specifically hollow PtPd nanocubes with high-index faces that they prepared. Hollow PtPd nanocubes have been demonstrated to reduce the ROS level of cells after radiation (4 Gy) and improve the survival rate of radiated mice (7.2 Gy), which can significantly increase from 0 to 30% after PtPd treatment [84]. Recently, compared with Pt and PtPb nanocubes, ternary PtPdRh nanocubes exhibited a better CAT-like activity. Treatment with PtPdRh nanocubes considerably enhanced cell viability by 94% and animal survival rate by 50% under high-energy γ radiation exposure (Fig. 11a) [85]. The Au-Pt NCs can be more readily ingested by human skin cells, scavenging ROS generated by UV light and preventing cellular damage [87]. Wang et al. prepared a spray of Pt NPs that effectively removed ROS induced by UV light through CAT/POD/SOD-like cascade catalysis, thereby alleviating the photoaging problem of the skin (Fig. 11b) [20]. These studies collectively demonstrate the significant potential of Pt nanozymes as radioprotective agents across diverse applications [89]. While Pt nanozymes show excellent radioprotective effects in preclinical models, their long-term biodistribution, potential metal accumulation, and the optimal timing of administration (pre- vs. post-irradiation) for maximizing efficacy and minimizing interference with radiotherapy need further systematic evaluation before clinical translation.

Fig. 11.

Pt nanozymes for the repair of radiation damage. (a) Hollow PtPdRh nanocubes eliminates radiation-induced ROS damage. Reproduced with permission from [85]. (b) Ultra-small Pt nano-enzymatic spray for photoaging treatment. Reproduced with permission from [20]

Drug-induced or chemical-induced toxicity

Some clinical drugs of abuse have been demonstrated to induce organ-specific toxicity, a phenomenon that may involve the involvement of ROS. This includes the hepatotoxicity observed in individuals exposed to acetaminophen, nimesulide, quinolones, and penicillin’s [90], the nephrotoxicity associated with vancomycin, acrylic acid, and anandamide [91, 92], and the neurotoxicity linked to paclitaxel [93]. In contrast, Pt nanozymes exhibit multiple antioxidant functions and a longer half-life, providing organisms with a more durable antioxidant capacity [94, 95]. For instance, Pt@PCN222-Mn nanozymes demonstrated superior efficacy in attenuating dextran sodium sulfate (DSS)-induced colitis in mice compared to the equivalent dose (0.5 mg/kg) of the small-molecule drug 5-ASA [96]; Pt/Co-SA-NSG nanozymes proved highly efficacious in alleviating H₂O₂-induced osteoarthritis [56]. In the He-CAP-induced oxidative stress model, the Pt NPs demonstrated effectiveness in reducing H₂O₂-induced osteoarthritis by inhibiting ROS-mediated [Ca²⁺]_i release and Fas receptor activation, thereby reducing the expression of Caspase-3 and Caspase-8. This, in turn, prevented the loss of matrix metalloproteinases and inhibited apoptosis [97]. The application of Pt nanozymes against organ-specific toxicity requires precise targeting to the injured organ (e.g., liver, kidney) to avoid unintended redistribution. Their long-term safety profile and potential interactions with the implicated drugs themselves remain to be fully elucidated.

Inflammatory bowel disease (IBD)

IBD is a non-specific inflammatory disease of the intestines, encompassing ulcerative colitis (UC) and Crohn’s disease (CD) [98]. The onset and progression of IBD is frequently linked to oxidative stress. For instance, infliximab and adalimumab is recommended by the clinical community, which are based on anti-inflammatory small-molecule medicines, have limited therapeutic efficacy, and cause serious complications [99]. Pt nanozymes have been demonstrated to possess the capacity to disrupt the detrimental cycle of oxidative stress and inflammation by eradicating ROS, a process that is catalysed by the CAT/SOD-like cascade [46, 96, 100, 101]. For example, Wei et al. used the CeO₂@Pt nanozymes to halt IBD progression by downregulation of the pro-inflammatory cytokines [100]. Wei et al. constructed a nanozyme (Pt@PCN222-Mn) with two catalytically active centres to target ROS overexpressed in the inflammatory milieu of IBD [96]. The cascade of the two catalytically active centers effectively cleared the ROS, and the treatment alleviated two types of IBD (UC and CD).

The route of administration thus plays a pivotal role in the design of nanozymes for the treatment or monitoring of IBD (Fig. 12a). For instance, when administered orally, Pt nanozymes with negatively charged surfaces are designed to specifically target the inflamed mucosa of IBD [102]. A typical example is the nanosensor PPNCP (negatively charged surface), which is capable of targeting inflammatory bowel segments and releasing ultra-small platinum nanoclusters (Pt NCs) at the damaged site to monitor changes in inflammatory bowel inflammation (Fig. 12b) [103]. Furthermore, some nanozymes have been developed for intravenous administration in the treatment of IBD. This is since the deterioration of IBD is accompanied by a significant influx of neutrophils, which release inflammatory mediators to recruit more neutrophils or other defense cells [104]. Some therapeutic strategies for neutrophils to control the exacerbation of inflammation include promotion of inflammation driven by neutrophils’ extracellular traps and inhibition of neutrophils’ “reverse migration” [105, 106]. For example, Zhang et al. developed PM@Pic/PtCD@NP through biomimetic modification with a platelet membrane. This nanozyme hitches rides on neutrophils to reach the inflammation site and releases its cargo to inhibit neutrophil swarming (Fig. 12c) [107]. Intravenous administration of PM@Pic/PtCD@NP partially reversed and prevented intestinal inflammation and repairing intestinal barrier dysfunction in mice by exerting antioxidant enzymes (SOD/CAT-like activities). For orally administered Pt nanozymes, stability in the harsh gastrointestinal environment, efficient targeting to inflamed mucosa amidst dense microbiota, and long-term intestinal safety are key translational hurdles. Intravenously administered neutrophil-hitchhiking strategies face challenges in scale-up manufacturing and controlling off-target immunomodulation.

Fig. 12.

Route of administration for IBD. (a) Schematic of oral and tail vein injection of Pt nanozymes treatment in IBD. (b) Oral PPNCP to monitor changes in IBD inflammation. Reproduced with permission from [103]. (c) Tail vein injection of PM@Pic/PtCD@NP for IBD. Reproduced with permission from [107]

Liver injury (LI)

LI is widespread hepatocyte necrosis and acute liver function deterioration in patients [108]. LI has a strong relationship with the overproduced ROS, which can effectively be eliminated by Pt nanozymes [109, 110]. For instance, Cui et al. prepared PbPt@MnO₂ nanoprobes (PPM NPs), which has POD/CAT/SOD-like activities [109]. PPM NPs alleviate the deterioration of LI by scavenging excessive ROS, inhibiting inflammatory cytokines, and decreasing activation of macrophage cells. Liu et al. designed a highly active nanozyme (Pt@CNDs), which has SOD/CAT-like specific activities of 12,605 U/mg and 3172 U/mg, respectively [110]. Pt@CNDs was effectively enriched in the hepatic site after 3 h of injection through the tail vein. Once pre-treated with Pt@CNDs, the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and the decreased liver necrotic areas of mice were significantly reduced (Fig. 13a). Although the potential of Pt nanozymes for liver repair and protection holds great promise, achieving targeted accumulation at hepatic lesion sites and exerting therapeutic effects remains a significant challenge. This is particularly true for chronic conditions or strategies requiring repeated dosing, which necessitate more comprehensive drug safety assessments.

Fig. 13.

Pt nanozymes mechanisms of treatment of liver injury, liver ischemia-reperfusion, and liver fibrosis. (a) Pt@CNDs alleviates liver injury by scavenging free radicals. Reproduced with permission from [110]. (b) Pt-iNOS@ZIF alleviates liver ischemia-reperfusion by reactive oxygen species clearance and NO regulation. Reproduced with permission from [21]. (c) APNH NTs alleviates liver fibrosis by eliminated reactive oxygen species, inhibit HSCs activation, downregulating NOX-4 and inhibitor of TIMP-1. Reproduced with permission from [114]

Liver ischemia-reperfusion injury (IRI)

Liver IRI occurs due to the cessation and restoration of blood supply, which severe liver injury [111]. Liver IRI is a pathological process involving multiple factors, which activation of macrophages caused by oxidative stress and hypoxia [21]. In a hepatocyte IRI model, Pt nanozymes were observed to effectively converge on the liver site, scavenging free radicals such as O₂^{• -} and inhibiting the expression of ALT and AST in plasma [112]. Furthermore, the addition of nitric oxide synthase (iNOS) and Pt NPs with SOD/CAT-like properties resulted in the construction of Pt-iNOS@ZIF (Fig. 13b) [21]. Pt-iNOS@ZIF was found to greatly reduce oxidative stress-induced damage, inhibit cell apoptosis, and reduce the expression of proinflammatory cytokines, leading to effective protection of liver IRI by eliminating ROS with generated O₂, which further promoted the production of NO via the catalysis of iNOS. For acute and severe liver injuries, not only does enhancing the targeted accumulation of Pt nanozymes at the lesion site and evaluating therapeutic efficacy require attention, but it also demands rigorous evaluation of the biosafety of Pt nanozymes, including their potential impact on normal liver metabolism and clearance pathways from hepatic tissues.

Liver fibrosis

Liver fibrosis is a dynamic and reversible self-healing wound response to chronic liver injury. However, chronic liver injury is usually accompanied by ROS-mediated oxidative stress, thereby accelerating the progression of liver fibrosis [113]. The main characteristic of liver fibrosis is excessive hypoxia, which is involved in liver fibrosis by affecting the imbalance of extracellular matrix (ECM) metabolism. Thus, Pt nanozymes with multiple catalytic activities capable of ROS elimination and hypoxia alleviation present a promising strategy for effective liver fibrosis therapy [114, 115]. A typical example is Li et al. developed that nilotinib (NIL)-loaded hyaluronic acid (HA)-coated Ag@Pt nanotriangular nanozymes (APNH NTs), which efficiently eliminated intrahepatic ROS by SOD/CAT-like activities, thereby downregulating the expression of NADPH oxidase-4 (NOX-4) and inhibiting HSCs activation. Importantly, the oxygen produced by the APNH NTs further alleviated the hypoxia and inhibitor metalloproteinase-1, and exhibited significant antifibrogenic effects (Fig. 13c). The dynamic and hypoxic microenvironment of fibrotic liver poses a dual challenge: ensuring deep penetration of nanozymes into fibrotic tissue and maintaining their catalytic activity long enough to break the cycle of oxidative stress and HSC activation. Long-term antifibrotic efficacy and safety are yet to be proven.

Osteoarthritis (OA)

OA is a degenerative disease that is characterized by the degeneration of cartilage, the degradation of the matrix and the inflammation of the synovial membrane [116–118]. Among these, oxidative stress induced by the inflammatory response i n the joint cavity represents a significant therapeutic target for OA. However, conventional oral exogenous anti-inflammatory medicine includes glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), which are unable to penetrate the joint space [119, 120]. By contrast, Pt nanozymes can overcome joint barriers and mimic POD/CAT/SOD-like activities, regulating ROS and RNS levels and restoring redox balance. This makes them a promising treatment strategy against [17, 56, 120–126].

Furthermore, inflammation induces synovial vascular hyperplasia, which accelerate the clearance of drugs from the joint cavity. These variations in conditions make intra-articular injection of nanozymes is an ideal mode of drug delivery [127]. For example, Zhang et al. developed PtCuO_X/CeO_2−X nanozymes as highly efficient SOD/CAT-like for OA therapy (Fig. 14a) [123]. On one side, Doping Cu and Pt on CeO₂ significantly increased the Ce³⁺/Ce⁴⁺ ratio to enhance the oxygen vacancies to promoting electron transfer, decreased the reaction activation energy, improving the SOD/CAT-like activity (Fig. 14c). On the other side, CeO₂ (111) surface promoted the homogeneous dispersion of Cu and Pt, thereby exposing the active centers (Fig. 14b). Besides, PtCuO_X/CeO_2−X nanozymes have excellent photothermal conversion efficiency (55.41%) (Fig. 14d), which effectively scavenged intracellular ROS and RNS in chondrocyte (Fig. 14e). In vivo, PtCuO_X/CeO_2−X nanozymes inhibited the ROS/Rac-1/NF-κB signaling pathway to remodel the OA therapy (Fig. 14f). Ma et al. A study demonstrated that Pt@PCN222-Mn nanozymes can alleviate the progression of temporomandibular joint osteoarthritis by inhibit the ROS-NF-κB and mitogen-activated protein kinase signaling pathways [124]. Wang et al. construct a bimetallic metal-organic framework (Pt@ZIF-8@La), which efficient scavenging of ROS and promote osteogenic mineralization by upregulating the ratio of the osteprotegerin/receptor activator of the NF-κB ligand to osteogenesis [121].

Fig. 14.

PtCuO_X/CeO_2−X nanozymes scavenge ROS in chondrocytes and treat OA by intra-articular injection. (a) A diagrammatic representation of PtCuO_X/CeO_2−X nanozymes treat OA. (b) Elemental mapping images of PtCuO_X/CeO_2−X. (c) Differential charge density map of PtCuO_X/CeO_2−X and calculation of the oxygen vacancy formation energy of CeO₂ and PtCuO_X/CeO_2−X. (d) Photothermal images. (e) Chondrocyte staining with various ROS (O₂^•−, •OH, and NO) assay kits. (f) Safranin O staining of knee joints at 4 and 8 weeks. Reproduced with permission from [123]

Furthermore, during OA progression, ROS/RNS are closely related to the respiratory electron transfer chain pathway of oxidative phosphorylation [128, 129]. Meanwhile, excessive ROS also promoted the overexpression of many inflammatory factors, which in turn leaded to abnormal cellular energy metabolism and OA deterioration [130, 131]. For example, Zhao et al. demonstrated that Pt SA/C₃N₄ could help reverse the oxidative stress-induced joint cartilage damage, which inhibited NDUFV2 of complex 1 and MT-ATP6 of ATP synthase, to reduce ROS/RNS and promote ATP production [17]. Zhao et al. showed excellent SOD/CAT-like catalytic activity using dual-activity-center Pt/Co-SA-NSG nanozymes, which could significantly restore mitochondrial function, regulate ATP level, reduce inflammatory factors level to relieved the OA with a 54.54% reduction in Pelletier score [56]. Intra-articular injection, while direct, faces issues of rapid clearance due to synovial hyperplasia. Developing formulations with prolonged joint residence time (e.g., using hydrogels) is crucial. The long-term effects of residual Pt in the joint cavity on cartilage and synovium need thorough assessment.

Gouty arthritis (GA)

GA is an inflammatory arthritis that is characterized by severe pain and complications. Hyperuricemia is the principal factor in the development of GA. NSAIDs, colchicine, and glucocorticoids provide effective relief of inflammation and pain [132, 133]. However, the potential for severe adverse effects restricts its broader application [134]. Uricase can degrade urate relief GA, and is significantly less toxic than first-line medicines [135]. For example, Sha et al. used HMPB-Pt@MM exhibits urate oxidase-like activities, continuously metabolizing locally elevated uric acid, eliminating ROS, and reducing infiltration of inflammatory macrophages (Fig. 15a) [136]. The hybrid nanozymes can inhibit the formation of urate based on the ARP-PtNCs nanozymes, which have the potential in GA therapy (Fig. 15b) [137]. However, urate metabolism in the arthrosis environment also leads to H₂O₂ accumulation. Thus, Shi et al. adopted a cascade reaction between the degradation of uric acid and timely elimination of H₂O₂ using uricase and CAT-like nanozymes-Pt/CeO₂ nanozymes (Fig. 15c) [138]. Pt/CeO₂ nanozymes markedly alleviate pain along with joint edema. Similarly, the PbPt₃ HNC surface accelerates the uric acid oxidation by facilitating H₂O₂-to-O₂ conversion and subsequent removal of H₂O₂ [139]. Zhang et al. developed a smart mesosystem-D-N[EM2], which encapsulates liposomes loaded with a combination of uricase, Pt-in-hyaluronan/polydopamine nanozyme, and resveratrol [22]. This approach not only ensures the safe and effective elimination of overexpressed uric acid and H₂O₂ in the joints, but also facilitates the reprogramming of the cellular inflammatory immune microenvironment and remodeling of the immune barrier. The success of uric acid and H₂O₂ cascade catalysis relies on sustained enzyme-like activity at the joint. Challenges include preventing the inactivation of nanozymes by protein coronas in synovial fluid and managing potential inflammatory responses to chronic degradation products.

Fig. 15.

The Pt nanozymes used to treat GA. (a) Schematic illustration of HMPB-Pt@MM relieving GA by degrading uric acid. Reproduced with permission from [136]. (b) Schematic illustration of uric acid degradation by ARP-PtNCs nanozyme. Reproduced with permission from [137]. (c) Schematic illustration of Pt/CeO₂ nanozyme by self-cascade uricase/catalase alleviate GA. Reproduced with permission from [138]

Rheumatoid arthritis (RA)

RA is characterized by chronic inflammation of the joints, damage to cartilage and bone [140]. Although the advent of targeted antirheumatic drugs like methotrexate has notably improved the clinical outlook in RA patients [141]. However, some of the patients did not do well. Synovial hypoxia and ROS accumulation induced macrophage polarization was a key factor in RA [142, 143]. Xie et al. used BSA-BR-Pt NPs to eliminate ROS and simultaneously generate O₂ in the knee and ankle joint of RA [144]. BSA-BR-Pt NPs treatment exhibited superior effects, which significant improvements in RA. BSA-BR-Pt NPs induced a re-polarization of hypoxic M1 macrophages to M2 macrophages. Dong et al. develop a Janus nanoplatform (Janus-CPS) [145]. Compared to the core-shell counterpart, the Janus nanoplatform is more able to expose the active site, which enhances the ROS scavenging capability of CeO₂-Pt nanozymes. Furthermore, micheliolide is loaded into the Janus nanoplatform with nanozymes for efficient RA treatment.

It is noteworthy that excessive inflammation induces the proliferation of synovial and meniscal blood vessels, which accelerates the removal of the drug from the joint cavity. The need for frequent administration of the drug exacerbates the risk of systemic toxicity. It is therefore evident that more rigorous standards must be applied concerning the intra-articular administration of pharmaceutical agents. This may be achieved through the utilization of innovative techniques, such as the incorporation of injectable and biodegradable hydrogels or microspheres, which can facilitate the precise localization of the site of inflammation and ensure the delivery of targeted treatment. Beyond scavenging ROS and repolarizing macrophages, a major challenge is achieving selective targeting to hypertrophic synovium while sparing surrounding cartilage and bone. The complexity of RA pathogenesis also demands combination strategies, raising concerns about complex product design and regulatory approval.

Ocular diseases

Ocular diseases are complex and multifaceted, involving oxidative stress, characterized by an imbalance between the production of ROS and the body’s ability to clear. The overexpression of ROS leads to cellular and molecular damage, including photoreceptors (PRs) degeneration, retinal neovascularization disorders, and cataract [146–152]. The optic rod and cone PRs in the retina exhibit a high frequency of oxidative metabolism in vivo, rendering them highly susceptible to oxidative damage. This vulnerability can lead to the development of cellular lesions and inflammatory responses. Li et al. synthesized antioxidative Pt NPs to treat PRs [150]. The intravitreal injection of Pt NPs significantly reduced cell apoptosis, maintained retinal structure, and preserved retinal function in a mouse of light-induced retinal degeneration (LIRD) (Fig. 16a). Furthermore, Fabio et al. propose the Pt nanozymes as a therapeutic tool for age-related macular degeneration (AMD) [146]. Pt nanozymes administered after light damage significantly preserved the number of PRs and inhibited the inflammatory response to degeneration, and enhanced PRs survival and visual performances in degenerated retains (Fig. 16b). The retinal vascular system plays an important role in maintaining normal eye function. However, retinal neovascularization is typically accompanied by hypoxia-induced oxidative damage. Yang et al. developed Pt@MitoLipo, which can alleviate hypoxia and eliminate excess ROS by SOD/CAT-like activities for retinal neovascularization disease therapy (Fig. 16c) [151]. owever, drug injections often cause great discomfort and pain. Gong et al. developed the eye drops based on noninvasive routes, which Pt nanoclusters coated with cell-penetrating peptide (TAT) conjugated dextran (DTPNGs), which have the ability of corneal permeation (Fig. 16d) [149]. DTPNGs performed the antioxidant capacities to protect lens epithelial cells from ROS damage, and inhibited α-crystallin glycosylation destruction in vitro. In vivo, the stage of the cataract was delayed after administration of DTPNGs eye drops (Fig. 16e). For intravitreal injections, retinal biocompatibility and potential phototoxicity (if used with light) are concerns. While eye drops offer non-invasiveness, their corneal penetration efficiency and retention time on the ocular surface are significant limitations that need formulation breakthroughs.

Fig. 16.

The Pt nanozymes used to treat ocular diseases. (a) Pt NPs protect PRs from light-induced oxidative damage and the structure of the light-induced retina. Reproduced with permission from [150]. (b) PtNPs on the morphology of light-damaged retinas. Reproduced with permission from [146]. (c) Representative confocal images of retinal staining of IB4 and hypoxyprobe. Reproduced with permission from [151]. (d) Schematic illustration of diabetic cataract relief by DTPNGs drops. (e) The images of rats’ eyes at the 6th week and the 12th week in different groups. Reproduced with permission from [149]

Acute kidney injury (AKI)

AKI, a rapid decline in renal function, has multiple contributing factors, including is associated with the development of systemic inflammatory response mediated by excess ROS [153, 154]. Therefore, there is an urgent need to develop antioxidants with high renal accumulation and effective renal clearance to deplete RONS in the kidney [153, 155, 156]. For example, Huang et al. developed ultrasmall polyvinylpyrrolidone-coated Pt nanoparticles (Pt NPs-PVP) as CAT/POD/SOD-like to excellent ROS/RNS scavenging ability, which remarkably relieved the AKI mice [156]. Furthermore, Qian et al. encapsulated Pt nanozyme clusters (PtNCs) in macrophage membranes (MM) to develop a bionic nano-system (MM-PtNCs) to alleviate AKI by modulating oxidative stress and inflammation [155]. MM-PtNCs, on the one hand, retained inflammatory cytokine receptors on MM surface allowed the biomimetic nano-system to target renal inflammation and inhibit these pro-inflammatory cytokines to reduce inflammation; on the other hand, PtNCs exhibit ROS scavenging ability and alleviate oxidative stress in damaged cells and tissues, which can significantly reduce renal injury and restore renal function. Shang et al. designed an ultrasmall platinum-based pre-nanozyme (Pt_5.65S), which exhibits pH-activated exceptionally broad-spectrum ROS/RNS scavenging capabilities and significantly alleviates in mouse models of kidney ischemia-reperfusion injury and cisplatin-induced AKI (Fig. 17a) [153]. Pt_5.65S pre-nanozyme released Ptzyme and H₂S gas exhibits an endo-exogenous synergy-enhanced antioxidant treatment in acidic and inflammatory settings (Fig. 17b, c). The Ptzyme reduces oxidative stress and inflammation (Fig. 17d). While the released H₂S gas inhibits the activation of the NF-κB pathway, and enhances the expression of antioxidant molecules and promotes Nrf2 activation (Fig. 17e). In addition, Pt_5.65S pre-nanozyme restored the morphology of mitochondria in AKI and minimized kidney damage (Fig. 17f, g). The combination of RuPt nanozyme with quercetin demonstrated augmented antioxidant capacity and efficacious inhibition of oxidative stress, effectively alleviating glycerol- and cisplatin-induced AKI [157]. The metal-polyphenol nanomicelles (Pt/HK-NMs) affect by scavenging ROS to alleviate oxidative damage, inhibiting macrophage activation and release of inflammatory factors to regulate inflammation and sepsis-associated acute kidney injury [158]. Moreover, gold-platinum nanoparticles (AuPt NPs) have excellent ROS scavenging capacity (CAT/POD-like) to treat kidney ischemia reperfusion injury [159]. A key challenge is balancing renal accumulation for efficacy with ultimate clearance to avoid nephrotoxicity and a self-contradictory risk in AKI. The performance of nanozymes in the context of severely compromised kidney function and variable urinary pH must be carefully evaluated.

Fig. 17.

Pt_5.65S pre-nanozyme treat acute kidney injury. (a) Schematic illustration of Pt_5.65S pre-nanozyme therapeutic mechanisms on kidney ischemia-reperfusion injury and cisplatin-induced AKI. (b) ROS scavenging capability of Ptzyme. (c) Schematic illustration of ROS scavenging by Pt_5.65S nanozymes cascade. (d) Pt_5.65S representative laser confocal for intracellular ROS detection. (e) The expression of NGAL, Nrf2, GPX4, and TNF-α proteins was detected by WB in each group. (f) TEM images of renal mitochondria in the AKI and Pt_5.65S groups. (g) Masson staining of kidney tissues from different groups. Reproduced with permission from [153]

Chronic skin inflammation

Disorders of the cutaneous oxidative-antioxidant system represent a pivotal element in the pathogenesis of inflammatory skin diseases. There is evidence to suggest that maintaining redox homeostasis by inhibiting ROS production through the addition of antioxidant enzymes can alleviate or treat inflammatory skin diseases caused by oxidative stress [160–162]. For example, Li et al. developed twin-defect Pt nanowires (Pt NWs) with SOD/GPx/CAT-like activities and broad-spectrum ROS scavenging capability for the treatment of psoriasis and rosacea-like mice (Fig. 18a) [162]. Among these conditions, psoriasis is a chronic inflammatory skin disease that is characterized by an imbalance between the immune system and keratinocytes. In psoriasis, the positive feedback loop between the immune system and keratinocytes amplifies the inflammatory response, which contributes to disorders of the cutaneous oxidative-antioxidant system. Song et al. engineered platinum-doped carbon (positively charged) dots (Pt-CDs) to scavenge the extracellular circulating cell-free DNA (cfDNA) and overexpressed ROS, reversed the overactivation of the cGAS-STING pathway, and reversed homeostatic balance in psoriasis (Fig. 18b) [161]. Pt-CDs, on the one hand, can bind the cfDNA and scavenge ROS to avoid the activation of the cGAS-STING pathway and macrophage activation; on the other hand, Pt-CDs restored the function of keratinocytes and inhibited TNF-α/dsDNA-induced expression of chemokines (Fig. 18c). Meanwhile, Pt-CDs alleviated the psoriasis-like skin inflammation in mice by decreasing the cfDNA levels both in plasma and skin lesions, and reversed the elevated expression of STING and phosphorylated STING (Fig. 18d, e).

Fig. 18.

The Pt nanozymes used to treat chronic skin inflammation. (a) Pt NWs clears ROS mitigation psoriasis-like skin inflammation and rosacea-like skin inflammation. Reproduced with permission from [162]. (b) Schematic illustration of Pt-CDs reverses homeostatic imbalance of psoriatic inflammation by inhibiting cGAS-STING overactivation. (c) TEM image of Pt-CDs. (d) The STING and pSTING expression within skin lesions by Western Blot. (e) H&E image. Reproduced with permission from [161]

Skin aging induced by chronological or intrinsic factors, which is overproduction of ROS and of inflammatory factors for upregulating the expression of matrix metalloproteinases (MMPs) and promotes collagen degradation [163]. Utilizing antioxidants and anti-inflammatory nanozymes constitutes effective strategies for mitigating the impact of skin aging [20, 164, 165]. PAPLAL (a mixture of Pb and Pt nanoparticles) is a potentially tool for the treatment of skin aging-related diseases by SOD/CAT-like activity [165]. Zeng et al. demonstrated that ultrasmall Pt NPs coated with polyvinylpyrrolidone, which can effectively scavenge ROS, inhibit macrophage polarization to decrease the expression of inflammatory factors, and downregulate MMPs to regenerate type I collagen to alleviate UV-induced skin photoaging [20]. For topical applications, skin barrier penetration and long-term local tolerance are primary concerns. The potential for Pt nanoparticles to penetrate deeper layers or even enter systemic circulation through damaged skin requires careful safety evaluation, especially for chronic conditions like psoriasis.

Parkinson’s disease (PD)

PD is a neurodegenerative disease, and its pathogenesis is closely related to the abnormal aggregation of -synuclein (-syn), loss of dopaminergic neurons, and ROS-induced oxidative stress [166, 167]. Currently, the therapeutic drugs for PD focus primarily on Anticholinergic drugs, levodopa (L-dopa), amantadine, DA agonists, and monoamine oxidase B (MAOB) inhibitors [168]. However, despite vigorous reports, few methods effectively inhibit the progression of PD. Some evidence suggests that ROS and mitochondrial dysfunction promote the generation and accumulation of -syn [169]. In addition, the possible transport of -syn to microglia to elicit M1 polarization, which ultimately accelerates the release of inflammatory factors and aggravation of the PD process. Thus, the application of Pt nanozymes to solve the problem of accumulation of excess ROS and alleviate neuronal degeneration damage is expected to be an effective strategy for treating the symptoms and root causes of PD based on an antioxidant system [170–172]. For example, the tri-element nanozyme (PtCuSe nanozyme) is suitable for relieving SH-SY5Y cells damage and mitigating the behavioral and pathological symptoms in PD by SOD/CAT-like activities for cascade scavenging of ROS [171]. Fan et al. developed a dual synergetic nanoreactor by encapsulating dihydroquercetin (Que) and Pt nanozyme (Ptzyme) in mannitol modified poly (lactic-co-glycolic acid) nanoparticles (Que/Ptzyme@Man-PLGA) to alleviate the behavioral and pathological symptoms of PD [173]. The Que/Ptzyme@Man-PLGA can effectively scavenge ROS and promote the transformation of microglia into the anti-inflammatory M2 phenotype.

However, common nanozymes can only play a temporary role in scavenging excess ROS existing in the extracellular and cytoplasm, but cannot fundamentally remove the source of ROS production, which severely limits their practical effect of eliminating the deterioration of PD. Forming a large number of ROS when the mitochondria function abnormally. Thus, it is possible to eliminate ROS from the source by removing mitochondria at the lesion continuously produce ROS. Zheng et al. report the efficient ROS scavenging of RVG29@AHM@Pt/CeO₂ nanozyme, which recruited the blood-brain barrier (BBB) and entered the site of neuroinflammation and inducing mitophagy and achieving improvement of motor and nonmotor symptoms in PD (Fig. 19a) [172]. In particular, the RVG29@AHM@Pt/CeO₂ nanozyme can break down existing ROS and induce mitochondrial membrane potential depolarization by interfering with the α-glycerophosphate shuttle pathway and malate-aspartate shuttle pathway, promoting the self-clearance of dysfunctional mitochondria, and thus eradicating the source of ROS generation (Fig. 19b). The strategy of radically eliminating neuroinflammation by inducing mitophagy in neurons achieves improvement of motor and nonmotor symptoms (Fig. 19c).

Fig. 19.

RVG29@AHM@Pt/CeO₂ nanozyme improvement of PD by inducing autophagy of abnormal mitochondria. (a) Schematic diagram of RVG29@AHM@Pt/CeO₂ nanozyme synthesis, and the mechanism of inducing abnormal mitophagy, and improving PD motor and nonmotor symptoms. (b) Representative flow cytometric images and laser confocal for detecting changes in Δѱm. (c) Representative images of the walking paths (swimming paths) of PD mice from different groups in the open field test (swimming test). Reproduced with permission from [172]

However, the BBB, an innate protective physiological barrier in blood and brain tissue, has been demonstrated to block more than 98% of drugs from entering the nociceptors [174]. The question of how to safely and reversibly open the blood-brain barrier has become a prominent area of research in the context of treating PD. Fan reports nanozyme-integrated metal-organic frameworks (Ptzyme@L-ZIF and Ptzyme@D-ZIF) with excellent antioxidant activity and chiral-dependent BBB transendocytosis for treatment of PD [175]. Especially, Ptzyme@D-ZIF reduces behavioral deficits and pathological changes in PD mice by clathrin-mediated and caveolae-mediated endocytosis across the BBB.

Braak’s staging theory posits that pathogenic α-syn is a prion-like protein [176]. ROS are a pivotal trigger for the proliferation of pathogenic α-syn. Mao et al. results show that PtCu NAs can significantly inhibit α-syn pathology, cell death, and neuron-to-neuron transmission by scavenging ROS in primary neuron cultures [177]. Furthermore, the PtCu NAs can effectively inhibit α-syn spreading induced by intrastriatal injection of preformed fibrils. Fighting prion-like proliferation through Pt nanozymes will likely be an effective therapeutic strategy for treating Parkinson’s disease and other prion-like protein diseases. The foremost challenge is efficiently crossing the BBB without compromising its integrity. Once in the brain, achieving neuron- or microglia-specific targeting, mitigating any neuroinflammatory side effects, and ensuring biodegradable or clearable designs are critical for clinical advancement.

Other inflammatory diseases

In addition to this, Pt nanozymes can alleviate a variety of inflammatory diseases formed by the build-up of ROS in the body, including myocardial ischemia-reperfusion injury, neurodegeneration, Alzheimer’s disease, androgenetic alopecia, and ear inflammation [23, 178–181]. For example, Shen et al. designed a PtsaN-C nanozymes to enhance antioxidative functions in eliminating ROS during myocardial ischemia-reperfusion injury [23]. PtsaN-C nanozymes significantly reduce cardiac injury, decrease infarct volume, and improve cardiac function after myocardial ischemia-reperfusion injury by scavenging ROS and reducing apoptosis induced by oxygen-glucose deprivation/reoxygenation injury.

Pt nanozymes with pro-oxidant activity

Pt nanozymes are employed in the treatment of specific diseases through the scavenging of ROS that are excessively produced by organisms in pathological states, and similarly, through the generation of ROS for therapeutic purposes. In other words, OXD/POD-like activity, which generates ROS and thereby inflicts oxidative damage on pathogens or cancer cells, has a beneficial therapeutic impact in the context of antimicrobial and antitumor treatments.

Antitumor

The TME exhibits distinctive characteristics, including hypoxia, acidic pH, and elevated levels of reduced glutathione (GSH) and H₂O₂, which collectively create a conducive environment for tumor proliferation, invasion, migration, adhesion, and neovascularization. This makes cancer a challenging disease to cure and prone to recurrence [182]. Excitingly, this is the target and basis for the pro-oxidant anti-tumor effects of Pt nanozymes. Pt nanozymes have the potential to kill or inhibit tumor cells by targeting them in a number of ways, including catalyzing ROS production, consuming endogenous reducing substances, and activating autoimmune functions. Concurrently, Pt nanozymes enhance the efficacy of radiotherapy, chemotherapy, phototherapy, and immunotherapy by responding to the characteristics of TME, thereby overcoming tumor tolerance and improving anti-tumor effects.

Improvement of hypoxia

Prior research has demonstrated that the majority of solid tumors exhibit a markedly hypoxic state, and the alleviation of this hypoxia can markedly enhance the efficacy of tumor therapy [183]. Zhang et al. employed DPC@Pt@M nanomicelles, which realize the sonodynamic/chemo combined therapy of colon cancer [184]. Especially, Pt nanozymes acted as CAT/POD-like catalysts to decompose H₂O₂ in situ to generate O₂ and •OH, respectively, thereby alleviating hypoxia and enhancing anti-tumor effects. Meanwhile, Pt nanozymes possessed SOD-like activity to replenish the depleted H₂O₂ and to improve colon cancer therapy. Furthermore, hypoxia exacerbates ROS production, which in turn activates hypoxia-inducible factor-1α (HIF-1α) by activating cellular energy sensors. HIF-1α then induces immunosuppression and ultimately promotes tumor growth and metastasis [185, 186]. The ultra-small Pt nanoparticles (Pt nano) with highly corrosive susceptibility can efficiently promote O₂ accumulation for hypoxia reversal, leading to reduced HIF-1α expression, and enhancement of chemoimmunotherapeutic efficacy [187].

Furthermore, O₂ is also widely used in photodynamic therapy (PDT). The photosensitizer molecules in the high-energy excited state transfer energy directly to the surrounding ³O₂, generating cytotoxic ¹O₂ and promoting apoptosis of tumor cells [188]. However, hypoxia easily occurs in TME, induces tumor resistance to PDT. Recently, the strategy of using Pt nanozymes for in situ catalytic oxygen production to overcome tumor hypoxia and enhance the effect of PDT has become one of the most promising research directions. For example, Pt@PEG-Ce6 has an efficient tumor accumulation, catalyzing in situ the production of O₂ from H₂O₂ and down-regulating the expression of HNF-α in tumors, while Ce6 converts O₂ to ROS under laser irradiation [74]. Similarly, Pd@Pt-PEG-Ce6 effectively enriches at tumor sites and triggers the decomposition of endogenous H₂O₂ to O₂, thus resulting in a significantly enhanced PDT efficacy [189]. The Pt@COF-BDP, PCN-224-Pt, and ICPA can efficiently and continuously convert H₂O₂ to O₂, thereby increasing the efficiency of ¹O₂ and achieving efficient tumor inhibition [190–192]. Fang et al. designed a nano-Pt/VP@MLipo that was capable of converging on the tumor site (Fig. 20a) [193]. The nano-Pt (3–5 nm) was able to catalyze the production of O₂ from H₂O₂, which enhanced the effect of PDT (Fig. 20b, c). Concurrently, PDT resulted in augmented liposome membrane permeability, thereby enabling the release of greater quantities of nano-Pt. Nano-Pt, in turn, could penetrate more deeply into tumor tissues, facilitating the penetration of chemotherapy through the generated O₂, which effectively inhibited tumor invasion and lung metastasis (Fig. 20d, e).

Fig. 20.

The nano-Pt/VP@MLipo reverse tumor hypoxia for cancer chemophototherapy. (a) Schematic illustration of the fabrication of nano-Pt/VP@MLipo chemophototherapy performance in tumors. (b) TEM images of nano-Pt/VP@MLipo and catalysed decomposition of H₂O₂ to produce O₂. (c) CLSM detection of HIF-1α expression in 4T1 cells. (d) Temporal-spatial distribution of nano-Pt/VP@MLipo in tumor tissue. (e) The brown nuclei of proliferative tumor cells were stained with anti-PCNA antibody. Reproduced with permission from [193]

Furthermore, noble metal nanozymes had strong and tunable surface plasmon resonance effects, making them simple and effective photothermal agents for photothermal therapy (PTT) [194]. uch as Pt-Co, PtNC@ABP-HBVC, Pt-Te, Au₂Pt-PEG-Ce6, Pt₅₀Sn₅₀, CDs@Pt SAs/NCs@DOX, and Pt@Bi₂Te₃-PEG mainly focused on near infrared I-region (NIR-I) PTT [75, 195–200]. For example, Gong et al. constructed a novel nano-assembly CDs@Pt SAs/NCs@DOX, which exhibits excellent POD/GPx-like activity [197]. A dual enzymatic activity of CDs@Pt SAs/NCs@DOX that produces a large number of ROS and depletes excessive GSH in TME. Meanwhile, the synergistic effect of nano-enzymatic catalytic therapy is promoted by low-temperature PTT to enhance intracellular oxidative stress and regulate intracellular redox homeostasis to achieve good anti-tumor effects. However, near infrared II-region (NIR II) light, such as higher permissible exposure, deeper penetration, and lesser energy dissipation [201]. Furthermore, the plasma wavelength can be redshift by adjusting the Pt structure or combining it with other metallic materials. Such as, AuPt@MnO₂, TPP-Pt, Au@Pt-DOX-PCM-PEG, MPNPs@Cu_2−xSe-AS1411, Ti₃C₂Tx-Pt-PEG mainly focused on NIR-II PTT [202–206]. For example, the porous Pt shell introducing Au is constructed porous Au@Pt core-shell nanozymes, which absorb NIR II and are used to alleviate hypoxia and enhance the effects of chemotherapy and NIR II photothermal therapy [205]. Another typical example is that Yang et al. decorate Pt nanozymes on the Ti₃C₂ nanosheets to synthesize Ti₃C₂Tx-Pt-PEG [206]. The Ti₃C₂ nanosheet exhibits high NIR II absorbance, enabling satisfactory PTT. In TME, Pt nanozymes exhibited POD-like activity, which could catalyze the generation of ∙OH from H₂O₂ in situ to induce apoptosis and necrosis of tumor cells, and PTT could further enhance this trend. Blindly increasing the temperature of the PTT release will inevitably cause damage to the surrounding normal tissues. Moreover, the process of angiogenesis that occurs in response to hyperthermia-induced inflammation facilitates nutrient transport, thereby promoting tumor progression and metastasis [207]. Matching anti-inflammatory effects with anti-tumor is important in the PTT process. Zhang et al. employed Pt-doped prussian blue (PtPB) nanozymes with tunable spectral absorption, high photothermal conversion efficiency, and outstanding antioxidative activity [208]. Thanks to its antioxidant catalytic activity, PtPB inhibits tumor progression and reduces heat-induced inflammation. Furthermore, Zhang et al. designed Pt/polydopamine (PDA) nanozymes (PNP), which exhibit an increasing anti-inflammation effect with the elevated temperature caused by PTT [209]. This phenomenon can be attributed to the presence of ROS-scavenging Pt nanozymes within the PNP, where the activity of the Pt nanozymes increases with temperature. PNP can achieve better antitumor performance and effective inhibition of tumor relapse and cancer metastasis.

In the TME, hypoxia, which could directly affect the therapeutic effect of oxygen-dependent PDT. Furthermore, PTT can also inevitably damage normal tissues when high temperatures are used to ablate tumors. Nevertheless, it is challenging to eradicate or inhibit solid tumors through the use of either PDT or PTT as standalone treatments. Thus, the combination of PTT and PDT is now a popular trend. By combining PTT with PDT, PTT is able to improve by enhancing CAT-like activity to generate O₂ for the relaxation of tumor hypoxia, thereby enhancing PDT efficiency and producing significant superadditive effects. Such as, Fe₃O₄@PDA@Pt-PEG-Ce6, mPt@Au-IR808, TOh Au@Pt-PEG-Ce6/HA, AuNTP@Pt-IR808, Au₂Pt-PEG-Ce6, Pt-Mn-PEI, Au₂Pt@PMO@ICG, ICG-PtMGs@HGd, PCN-224/Pt/Cu²⁺, BSA@Au/Pt-IR808, Pt-carbon, and Pt-Ce6 [75, 210–220]. For example, the TOh Au was coated with Pt nanozymes to form a spatial separation structure, which enhanced the local surface plasmonic resonance and thus boosted the photocatalytic effect [217]. On the one hand, the structure of arris deposition adequately Pt improves the photothermal conversion efficiency, which greatly enhances the effect of PTT and improves the enzyme activity; on the other hand, the Pt in situ oxygen production improves the tumor hypoxia, enhances the effect of PDT and inhibits the tumor growth and development through the O₂ self-production and sales mode. Furthermore, Chen et al. synthesized a Au₂Pt@PMO@ICG Janus nanomotor (APIJNS), which can realize self-thermophoresis drive under the trigger of NIR, which can effectively enhance the active permeability and uptake of the APIJNS in the tumor, thus achieving efficient PTT/PDT/CDT synergistic therapeutic effect [219]. In addition, APIJNS exhibits efficient CAT-like activity, which can catalyze the production of O₂ from overexpressed H₂O₂ in TME, which not only alleviates the hypoxia within the tumor lesion, but also converts it into ¹O₂ to activate the photosensitizer ICG and enhance the effect of PDT for synergistic antitumor effects. Zhao et al. constructed oxygen-independent precision cancer phototherapy nanozymes CP1-NCs, which are the photothermally responsive phase change materials [221]. The 1,4-dimethylnaphthalene moieties in CP1-NCs can trap the ¹O₂ from 1,4-dimethylnaphthalene-functionalized Pt(II)-acetylide conjugated polymer (CP1) under NIR irradiation and form a stable endoperoxide. Subsequently, the CP1 photothermal effect triggered by NIR leads to a controlled phase transition and controlled release of ¹O₂, which can be used for oxygen-independent PDT in hypoxic tumors.

Phototherapy PPT and PDT, as the typical representative of non-invasive tumor treatment modality, exhibits many advantages [222, 223]. However, phototherapy is greatly hampered by the depth of tissue penetration of lasers and the apparent phototoxicity of photosensitizers, which hinders the resection of deep tumors and further clinical applications. To overcome the limitations of Phototherapy penetration. In 1989, Yumita and Umemura initially proposed sonodynamic therapy (SDT), which entails the utilization of energy delivered in the form of ultrasound (US) that traverses the soft tissues to achieve energy deposition in the target area. Additionally, the synergistic action of the cavitation effect with acoustic sensitizers is employed to generate ROS, which induces apoptosis in tumors situated deeply within the organism [224]. During SDT, sonosensitizers are the critical determinants for the efficiency of SDT. High-quality sonosensitizers should meet a number of needs during treatment, including ROS generation efficiency, biocompatibility of the material, and tumor targeting. However, conventional organic small-molecule sonosensitizers have the disadvantages of poor water solubility, high toxicity, and poor tumor targeting [225]. On the contrary, inorganic sonosensitizers display excellent stability, controllable morphology, and multifunctionality [226]. Such as, PtMo-Au, Pt/PCN-224(Fe)/PEG, Pt/BTO@MCMPs, Ti₃C₂-Pt, Zn/Pt SATs, Pt/CeO_2−XS_X, BiF₃@BiOl@Pt-PVP, TiO₂@Pt/GOx, MoN-Pt@PEG, CaCO₃@Pt-TiO₂, Pt-ZnO, CF@Pt, and Pt-B-P NPs [227–239]. However, inorganic sonosensitizers easily undergo electron-hole recombination pairs under US stimuli, which greatly limits ROS production and extremely reduces the therapeutic effect of SDT. Zhang et al. reported dual-component and dual-site single-atom Zn/Pt difunctional superimposition-augmented TiO₂-based sonosensitizers (Zn/Pt SATs), which improve the yield of ROS and thus enhance ferroptosis [234]. This is derived from the fact that the strongly coupled Zn and Pt atoms under US assist electronic excitation at the atomic level by increasing the electronic conductivity and excitation efficiency, respectively, thus effectively increasing the ROS yield. BiF₃@BiOl heterojunction enhances charge separation ability. In particular, the decoration of Pt nanozymes narrows the bandgap and alters the band positions and Fermi level of BiF₃@BiOl heterojunction, which can effectively mitigate the rapid recombination of electron-hole pairs and facilitate a cascade reaction of ROS, and enhance the efficacy of tumor treatment [235]. Similarly, compared to TiO₂, the band gap of TiO₂@Pt is outstandingly decreased to 2.9 eV. The energy structure optimization enables a more rapid generation of ¹O₂ and •OH by TiO₂@Pt under US irradiation [238]. The development of targeted drug delivery systems has been enabled by the unique properties of nanomaterials and the diverse range of enzymatic activities. These systems have been engineered to enhance multidrug loading capacity, alleviate TME hypoxia, and facilitate the enrichment of sonosensitizers at tumor sites, such as CCP@HP@M, DPC@Pt@M, CLP@HP-A, and BP-M-PtCu₃ [184, 240–242].

Overexpression of H₂O₂

The study demonstrated that the levels of H₂O₂ in tumor cells (5 µM to 1.0 mM) were significantly higher than in normal cells (less than 0.7 µM) [243]. Consequently, Pt nanozymes with POD/OXD-like activity can target tumors by catalyzing the production of •OH and O₂^•− from H₂O₂ and O₂, thereby killing tumor cells. For example, PtPdRuRhIr US-HEANPs exhibit excellent POD-like activity and can catalyze the endogenous H₂O₂ to produce highly toxic •OH for tumor treatment [63]. Another example, Pt/C nanozymes exhibit POD/OXD-like activity to transfer H₂O₂ and O₂ in the tumor to ROS respectively for antitumor [244]. Ling et al. reported Pt nanozymes (NMPNs) inhibit the recruitment of nucleotide excision repair (NER)-associated factors by targeting the nucleus of cancer cells and generating •OH and O₂^•− in situ, thereby significantly enhancing the overaccumulation of Pt-DNA adducts and apoptosis of tumor cells (Fig. 21) [245]. However, most solid tumors are highly hypoxic. Thus, another approach is to catalyze the H₂O₂ in TME by POD/OXD/CAT-like activity to generate •OH and O₂^•− and O₂. For example, PtFe@Fe₃O₄ exhibits POD/CAT-like activities in the acidic TME, thereby effectively killing tumor cells and alleviating hypoxia [246]. Other nanozymes with POD/OXD/CAT-like activity, such as Fe₃O₄/Pt-FLU@PEG, Pt/CeO₂-R, Pt@LC@RB, Pt nanozyme, and CPNS@Pt through catalysis to promote tumor apoptosis [247–251].

Fig. 21.

Schematic illustration of NMPNs-mediated concurrent DNA platination and oxidative cleavage to overcome Pt resistance of cancer. Reproduced with permission from [245]

H₂O₂ self-replenishment

Despite the elevated level of H₂O₂ in tumors relative to normal cells, the concentration of H₂O₂ in TEM remains inadequate to sustain the continuous production of •OH, which is essential for effective antitumor activity. It is therefore essential to provide the endogenous H₂O₂ required for continuous and effective stimulation of TEM to produce •OH by means of nanozymes. For example, Lin et al. designed a trimetallic alloy nanozyme AuCuPt-PpIX (ACPP), which exhibits five enzymes activities: glucose oxidase-like (GOD)/SOD/POD/CAT/GPx-like for the treatment of tumor with H₂O₂ self-replenishment properties (Fig. 22) [252]. The ACPP possessing SOD/GOD-like activities were able to catalyzing endogenous O₂^•− and glucose for continuous H₂O₂ supply in the TME accompanied by the collateral “starvation therapy” and a more acidic TME, which was conducive to subsequent enzymatic reactions. The produced H₂O₂ was then converted into O₂ by virtue of the CAT-like activity of the ACPP to relieve the hypoxic TME and compensate for the consumption of O₂ in the GOD-like catalysis process, thus resulting in the cyclic consumption of glucose and the self-supply of H₂O₂ substrates used to generate •OH. Meanwhile, the intrinsic GPx-like activity of ACPP constantly consumes GSH with the assistance of H₂O₂ and protection of generated ROS to break the antioxidant defense effect of the tumor and further inhibit GPX4 activity, ultimately promoting lipid peroxidation (LPO) accumulation and enhancing the ferroptosis effect. Similar examples, such as CoO@AuPt, PGMA, FeMOF/Pt/GOx, AuPt@SF, PCN-224/Pt/Cu²⁺, PtN₄C-SAzyme can not only disrupt the redox homeostasis in tumors through a series of self-cascade catalysis reactions but also achieve cyclic regeneration of the relevant enzyme substrates [31, 214, 253–256].

Fig. 22.

Schematic illustration of the preparation of the multimetallic alloy ACPP nanozymes and the proposed antitumor mechanism. Reproduced with permission from [252]

Overexpression of GSH

Tumors produce substantial quantities of reducing substances to counteract oxidative stress. Relevant studies show that the concentration of GSH in tumor cells (2–10 mmol/L) is approximately 1000 times greater than the extracellular GSH concentration (2–20 µmol/L) [257]. Some strategies take advantage of differences in GSH concentration to construct GSH-responsive prodrugs by introducing a sulfur bond that, in the presence of GSH, may achieve drug-responsive release at the tumor site and enhance anti-tumor effects. For example, Qian et al. prepared a GSH-responsive prodrug (PTX-SS-HPPH/Pt@RGD-NP) by introducing a disulfide bond, which enables drug release at the tumor site (Fig. 23a) [258]. Particularly, PTX-SS-HPPH/Pt@RGD-NP could achieve GSH-responsive drug release in TME, enhance the drug accumulation time and permeability at tumor sites in T24 subcutaneous tumor model and T24 orthotopic bladder tumor model (Fig. 23c, d, e). In addition, Pt nanozymes were introduced to produce O₂ and improve therapy for bladder cancer efficiency (Fig. 23b). Similar examples such as PHDT-Pt-In, CP5 NPs, Apt@NCTD@MON_Pt/Se, NP(3 S)s, Pt/BSO-MS-HA, and PP-SS-DA [259–264]. Another approach is to deplete GSH in TME via GPX-like. For example, PtPd nanozymes have diverse enzyme-like activities that not only alleviate hypoxia to reduce the invasive capacity of cancer cells, but also generate ROS, leading to significant cellular oxidative damage and triggering severe tumor cell apoptosis [265]. In addition, intrinsic GPx-like activity of PtPd nanozymes, which enables persistent GSH depletion and accumulation of ROS, induces redox dysregulation in tumors and leads to immunogenic cell death, thereby inhibiting tumor metastasis. Another strategy utilizes the reaction of the Pt(IV) prodrug with GSH, where Pt(IV) is reduced to Pt(II) while consuming GSH. For example, Yu et al. designed light-activatable liposomes (Pt/Ce6-LP), which reversal cisplatin resistance in tumors [266]. Furthermore, the depletion of GSH during the conversion from Pt(IV) prodrug to Pt(II) was found to prevent ROS depletion, thereby reshaping the redox balance between ROS and GSH in tumors, resulting in significant anti-tumor effects. Similar examples such as Pt(IV)NP-cRGD, UCNP/Pt(IV)-RGD, CuS@Pt(IV)@PEG, MOF-Pt(IV)@GOx, NP@Ev, Pt(IV)-crosslinked nanogels, Oxa(IV)-SS-OA, iAIO@NSe-Pt, PtHPs, CuS-Pt(IV)-PEG-FA, BT-4@PtPPNPs, Pt-CD-Ad@OU, San@Pt(IV)-DI-PEG@FCS, and DP through cytotoxic Pt(II) via GSH reduction, thereby promoting apoptosis in tumor cells [72, 267–279].

Fig. 23.

The PTX-SS-HPPH/Pt@RGD-NP used to treat bladder cancer. (a) Schematic illustration of PTX-SS-HPPH/Pt@RGD-NP for bladder cancer therapy under a 660 nm laser. (b) TEM image of PTX-SS-HPPH/Pt@RGD-NP. (c) Release behavior of PTX-SS-HPPH/Pt@RGD-NP at different concentrations of GSH. (d) In vivo fluorescence images of T24 tumor-bearing mice at the designated time points (1, 4, 24, 48 h). (e) In vivo bioluminescence images of treatment PTX-SS-HPPH/Pt@RGD-NP in T24 orthotopic bladder cancer model. Reproduced with permission from [258]

In addition to exhibiting high catalytic activity, nanozymes must be capable of accumulating in a highly efficient and selective manner at the tumor site. Presently, numerous laboratory investigations are predicated upon the utilization of intratumoral injections of tumors to facilitate the accumulation of nanozymes for antitumor purposes. Nevertheless, the clinical application of this approach is constrained by the fact that a considerable number of solid tumors are situated at deeper locations, rendering routine intratumoral injection impractical. An alternative approach would be to administer the nanozymes intravenously, which is more likely to be accepted by the scientific community. This requires the nanozymes to have a targeted and controlled release to the tumor site in order to achieve precise treatment in the target area while minimizing damage to normal tissue. This can be achieved by targeting receptors on tumor cells or using cell membrane-wrapping materials. One example is CLP@HP-A, which was prepared by Zhang et al. and specifically binds to the Galectin-3 receptor on the surface of thyroid cancer cells [240]. Mesoporous silica nano-assemblies containing Pt NPs (HA-PCD) were prepared by Ge et al. [280]. The interaction between HA modified on the surface of HA-PCD and CD44 on the membrane surface of cancer cells enhanced the targeting of tumor cells. The POD/OXD-like activity generated ROS, which achieved favorable therapeutic outcomes in a tumor-bearing mouse model. Zhang et al. constructed CCP@HP@M by doping hollow PDA with CAT-active Pt nanozymes, coating with cancer cell membranes, and loading CQ and Ce6, which enhanced CCP@HP@M targeting ability and optimized the acoustic-dynamic therapeutic effect in colorectal cancer [241]. ang et al. obtained nano-Pt/VP@MLipo by hybridizing nano-Pt/VP liposomes to RAW264.7 macrophage membranes, which facilitated their escape from the mononuclear phagocytosis system and enhanced tumor targeting [193]. Mao et al. employed a genetically engineered filamentous phage as a template to induce the synthesis of Pt nanozymes, which then acted as a targeting delivery vehicle to deliver the nanozymes and photosensitizer drugs to the tumor site for tumor therapy [281]. Qian et al. constructed PTX-SS-HPPH/Pt@RGD-NP by modifying the tumor-targeting peptide, Arg-Gly-Asp (RGD), on Pt NPs [258]. Upon irradiation with 660 nm near-infrared light, the PTX-SS-HPPH/Pt@RGD-NP exhibited specific accumulation in the bladder cancer site. The major translational challenges include achieving sufficient tumor-specific accumulation over healthy tissues (especially for intravenous delivery), overcoming the heterogeneity and adaptability of the TME that may diminish catalytic efficacy, and addressing potential long-term toxicity of Pt accumulation. Standardizing activity measurements across studies is also needed to compare nanozymes rationally.

Antibacterial

Bacterial infections have emerged as a significant global public health concern, with the misuse of antibiotics contributing to the emergence of drug-resistant bacteria. In comparison to traditional antibiotics, nanozymes have the capacity to produce highly toxic ROS in a number of ways that can directly affect the structure of bacteria. This results in lipid peroxidation damage, inactivation of functional proteins, and DNA strand breaks within the bacterial membrane, which effectively inhibits bacterial growth and proliferation [282]. This method of bacterial eradication, which does not alter the genetic material of the bacteria, renders bacteria unable to develop resistance through natural selection or genetic mutation [283]. Consequently, the possibility of developing drug resistance is significantly reduced. In light of these considerations, the development of simple, effective, long-lasting, and broad-spectrum antibacterial nanozymes has emerged as a promising therapeutic option to combat evolving bacterial drug resistance.

Bacterial infections

H₂O₂ solutions (0.5-3%) are widely used for routine wound disinfection and antibacterial. However, the bactericidal efficiency of the H₂O₂ solution was low, especially for bacteria with high CAT-like activity [284]. Thus, Pt nanozymes with excellent POD-like activity reduce the need for H₂O₂ dosage and improve the antibacterial effect [50, 285–291]. For example, the fabricated Pt hollow nanodendrites exhibited excellent POD-like activity, with the highly toxic •OH produced via POD-like activity inhibiting Escherichia coli (E. coli) and Staphylococcus aureus (S.aureus) by about 80% at very low dosages of H₂O₂ (0.01 × 10^{− 3} M) and Pt (7 × 10^{− 6} M) [50]. The AuPt NDs have POD-like activity, which was found to be 3.4 times higher than that of horseradish peroxidase (HRP) [291]. The in vitro antimicrobial results demonstrated that the inhibition rates against E. coli and S. aureus were 97.1% and 99.3%, respectively. Pt@PSi nanozymes exhibit excellent NIR photothermal effect and POD-like activity, achieving more than 95% bacterial inhibition, thus accelerating wound healing [285]. PtAu nanozymes have potent OXD/POD-like activity, generating large amounts of ROS that disrupt the bacterial respiratory chain, inhibit ATP synthesis, and impede bacterial energy metabolism, thereby completely inhibiting biofilm formation and promoting wound healing [290]. Similarly, BiPt nanozymes with OXD/POD-like activities, without additional H₂O₂, reduced bacterial counts and promoted elimination of carbapenem-resistant Enterobacter ales and methicillin-resistant Staphylococcus aureus in mice [292]. Moreover, combining POD-like nanozymes with GOx-like can provide an acidic environment and accelerate •OH to improve wound sterilization [293–295].

Diabetic wound ulcers

The broad-spectrum antibacterial mechanism of Pt nanozymes offers a technological foundation for treating complex infection scenarios (such as diabetic wound ulcers). The etiology of chronic diabetic wounds that are difficult to heal is multifaceted, including bacterial infections, uncontrolled accumulation of ROS, local hypoxia, and persistent inflammation [296–298]. Cutaneous wounds of diabetes are prone to bacterial infection due to their high-concentration glucose and abnormal pH physiological microenvironment [299]. Pt nanozymes with robust POD-like or OXD-like activity improve the antibacterial effect [300–303]. Building on the antibacterial advantages of Pt nanozymes, their application in diabetic wound therapy requires further resolution of microenvironment-specific challenges. For example, PtRu/C₃N₅ exhibited OXD-like activity, which exhibited broad-spectrum antibacterial efficacy and effectively inhibited the inflammation reaction, and is promising for accelerating cutaneous wound healing [302]. Another strategy catalyzes glucose into gluconic acid and H₂O₂ by exerting GOD-like or loaded GOD, which not only lowers the pH of the wound microenvironment to promote POD-like activity, but also replenishes the H₂O₂ substrate [304–309]. For example, Apt-PtNZ, GOD, and hyaluronic acid constitute “APGH”, which is released in the wound, and glucose oxidation upregulates local pH and supplements H₂O₂ for the in-situ generation of •OH on bacterial surfaces, effectively promoting diabetic wound healing [304]. Moreover, the scavenging of excessive ROS and alleviating hypoxia in diabetic wounds is a highly promising strategy to overcome stalled wound healing [310–312]. While nanozymes can mitigate bacterial resistance, ensuring their potent antibacterial activity in protein-rich biofluids (e.g., wound exudate) and preventing surface contamination remain challenging. For systemic applications, avoiding unintended cytotoxicity to host cells and understanding the immune response to chronic nanozyme exposure are critical safety considerations.

The dual antioxidative/pro-oxidative functionalities of Pt nanozymes originate from their pH-dependent enzymatic plasticity and microenvironment-sensing capacity. In acidic niches (e.g., tumors, pH 6.5), enhanced POD-like and OXD-like activities drive Fenton-like reactions that convert H₂O₂ into cytotoxic •OH, eliciting pro-oxidative effects [313]. Conversely, under alkaline conditions (e.g., chronic wounds, pH 7.5–8.9), CAT-like and SOD-like dominance enables ROS scavenging and hypoxia alleviation via H₂O₂ decomposition [314]. Notably, Pt nanozymes’ exceptional CAT activity exhibits dual biological relevance: while mitigating hypoxia, the generated O₂ fuels exogenous photosensitizers or sonosensitizers to produce ROS under photo-/sono-activation, dynamically switching from antioxidative to pro-oxidative modes (Table 4).

Table 4.

Cascade catalytic reactions of Pt nanozymes depend on pH and microenvironmental variations

Enzyme-like activities	Substrate regulation	Function output	Applications	Ref
SOD-like	O2•− → H2O2	Antioxidant	Inflammatory	[45, 84, 85, 87]
			Antitumor	[184, 187, 208, 240, 241, 252]
CAT-like	H2O2 → O2	Antioxidant	Inflammatory	[20, 96, 114, 155]
		Improve Hypoxia	Antitumor	[74]
POD-like	H2O2 (Low Concentration) → H2O	Antioxidant	Inflammatory	[97]
	H2O2 (High Concentration) → •OH	Pro-oxidant	Antitumor	[280]
			Antibacterial	[50]
OXD-like	O2 → O2•−	Pro-oxidant	Antitumor	[245]
			Antibacterial	[302]

Three synergistic strategies govern functional duality of Pt nanozymes: (i) Substrate-intermediate regulation: POD-like catalysis involves radical intermediates, enabling either •OH generation via Fenton-like pathways or H₂O₂ reduction to H₂O for ROS clearance. This bifunctionality is modulated by local H₂O₂/O₂ levels and enzyme concentration, with OXD-like activity being strictly O₂-dependent. (ii) Energy-responsive enhancement: inherent photothermal conversion and X-ray deposition capabilities amplify enzymatic kinetics under near-infrared/X-ray irradiation, synergizing photothermal/radiotherapy. (iii) Microenvironment remodeling: In pathologically alkaline environments (e.g., infected diabetic wounds), pathogenic ammonia secretion suppresses pro-oxidative activity. Strategic conjugation with glucose oxidase acidifies locales via gluconic acid production, reactivating POD/OXD-like cascades. Post-infection resolution, pH normalization shifts Pt nanozymes to CAT/SOD-mediated antioxidative repair. Furthermore, intervention timing dictates therapeutic polarity: pre-irradiation administration exploits Pt’s high atomic number (Z = 78) for radio sensitization, while post-irradiation delivery utilizes SOD/CAT-like activities to scavenge radiation-induced ROS and promote repair. This spatiotemporal switching unifies antagonistic redox applications (e.g., tumor ablation vs. anti-inflammation). Through rational material engineering (doping/conjugation) and external energy inputs (light/sound/heat), Pt nanozymes can be programmed to sense biomarkers (pH/hypoxia/temperature), advancing from passive microenvironment adaptation to active remodeling for precision nanomedicine.

Conclusions and outlook

In conclusion, Pt nanozymes demonstrate structural stability, control, and versatility, and exhibit SOD-like, CAT-like, POD-like, and OXD-like activities. They exhibit significant potential for modulating ROS therapy-related diseases. The dual antioxidant/pro-oxidant functionalities of Pt nanozymes stem from their microenvironment-responsive enzymatic plasticity.

Modulation of the redox enzymatic activity of Pt nanozymes

In acidic niches (e.g., tumors, bacterial biofilms), dominant POD/OXD-like activities convert H₂O₂/O₂ into cytotoxic ROS, eliciting pro-inflammatory oxidative burst to eradicate pathogens. Conversely, SOD/CAT-like supremacy scavenges excess ROS and repairs redox homeostasis, thereby resolving inflammation. This pH-driven “functional switch” is further amplified by external energy inputs (light/sound/heat), enabling spatiotemporal precision in inflammatory regulation. In addition, this review summarizes strategies for enhancing the activity of Pt nanozymes, including size control, morphology engineering, component doping, surface modification, and external field modulation. Size influences the intensity of enzymatic activity to some extent, which may be attributed to its effects on specific surface area, morphology, and the effective contact between substrates and active sites. Component doping alters the electronic structure by introducing heteroatoms or foreign elements, thereby enhancing existing active sites or creating new ones for synergistic catalysis. Surface modification is typically employed to improve the stability, dispersibility, and functionality of Pt nanozymes.The ultimate goal of these strategies is to further enhance the specific catalytic performance of Pt nanozymes for therapeutic applications. For the design of Pt nanozymes tailored to specific diseases, the following approaches can be considered. We provide brief research perspectives below:

• (i)Intravenously administered Pt nanozymes: Key factors include targeting efficiency, half-life, and size. It is essential to ensure that the nanozymes can reach the target site, achieve effective therapeutic concentrations upon arrival, and be efficiently cleared from the body post-treatment. Therefore, surface modification strategies and size control can be utilized to improve targeting capability, stability, and safety.
• (ii)Locally administered Pt nanozymes: For such routes, the catalytic activity of Pt nanozymes should be prioritized. Activity can be enhanced through component doping and size regulation. For instance, in antibacterial or antitumor applications, doping with metal elements such as Fe, Cu, Au, or Ag can promote ROS generation. In anti-inflammatory therapies, doping with elements like Ce, V, Se, or C can enhance ROS scavenging. Of course, each disease has its unique pathological characteristics, requiring a multifaceted approach to design Pt nanozymes with the most promising translational potential. Notwithstanding the considerable advances made by Pt nanozymes in antimicrobial, anti-inflammatory, and antitumor applications, the specific in vitro enzyme catalytic mechanisms underlying their therapeutic effects remain largely unknown. To illustrate, the generation of GSH from GSSH, catalyzed by GPx-like activity of nanozymes utilized in certain experiments investigating antitumor activity, is accompanied by the consumption of reducing substances and the scavenging of H₂O₂. It is yet to be determined whether this process contributes to the induction of oxidative stress in tumors. Nevertheless, it is irrefutable that GSH depletion renders tumor cells more susceptible to lipid peroxidation. Furthermore, ROS-producing nanozymes were employed as antimicrobials to eradicate infections at skin breaks. Nevertheless, it is evident that ROS is inherently unable to discern whether it is a bacterium or a cell that is the source of the attack. The indiscriminate nature of the attack increases the probability of inducing the simultaneous death of both the pathogen and the cell. It is therefore important to design pro-oxidant enzymes that are capable of selectively attacking pathogens, rather than mammalian cells. An in-depth consideration of the interrelationships between various microenvironments at different phases of the biological process is necessary to aid in the development of systemic and synergistic microenvironment-regulatory Pt nanozymes.

Toxicology of Pt nanozymes

The application of Pt nanozymes in the biomedical field remains contentious due to a scarcity of comprehensive toxicological data. Concerns particularly center on potential adverse effects such as Pt accumulation in organs like the liver and kidneys following high-dose or chronic administration, disruption of cellular ion homeostasis, and interference with normal cell signaling by non-specifically generated ROS. However, accumulating evidence also suggests that observed cellular damage in some experiments may often be attributed to various contaminants present in the experimental environment, including endotoxins, toxic capping agents, additives, or by-products from the synthesis process. Conversely, a substantial body of data indicates that Pt nanozymes exhibit favorable cytocompatibility and biosafety [11]. Specifically: In vitro, Iwahashi et al. [315] co-incubated Pt nanozymes with A549 and HaCaT cells and found no detectable release of Pt ions. Shirahata et al. [45] demonstrated that culturing TIG-1, WI-38, MRC-5, HeLa, and HepG2 cells with Pt nanozymes at concentrations up to 50 µg/mL did not induce cytotoxicity, oxidative stress, or cell death. Moglianetti et al. [316] evaluated cellular toxicity using Pt nanozymes at concentrations as high as 100 µg/mL, concluding that they exhibited excellent cytocompatibility. Further TEM imaging revealed that Pt nanozymes could be effectively internalized by cells without causing discernible damage. Pompa et al. [11] further summarized that there is currently no definitive evidence linking observed biological injury post-administration of Pt nanozymes specifically to released Pt ions. Importantly, regulatory bodies such as the U.S. FDA have acknowledged the safety of Pt in its zero-oxidation state, and the Japanese government has approved the incorporation of Pt nanozymes into daily consumer products and health supplements. Several Pt nanozyme-based products have even been employed in clinical settings, for instance, PAPRAL (Patent No. 3411195, 2003) is approved for treating burns, frostbite, and acute gastritis [165].

On the other hand, regarding the impact of in vivo accumulation, data suggest that intravenously administered ultrasmall Pt nanozymes (< 5.5 nm) can be effectively taken up and enriched by the kidneys and, due to their small size, efficiently excreted from the body without significant toxicity [156]. In contrast, larger Pt nanozymes may not be readily cleared renally and could be eliminated via alternative pathways (e.g., fecal excretion), potentially posing risks associated with metal accumulation and long-term toxicity. Therefore, future systematic investigations into their metabolic pathways, immunogenicity, and chronic toxicity profiles are imperative. While data derived from experimental models provide preliminary support for the safety of Pt nanozymes, a significant gap remains between these findings and requirements for clinical therapy or large-scale pharmaceutical manufacturing. Particular attention must be paid to long-term toxicity, rational drug design, and the purity of scaled-up production, necessitating meticulous evaluation using advanced characterization techniques to ensure the biosafety of synthesized Pt nanozymes.

Currently, novel therapeutic agents synthesized or modified through nanotechnology provide innovative strategies to address major disease crises facing modern society. However, nanotechnology-based nanomedicines, particularly platinum-based formulations, lack standardized synthesis protocols and an internationally harmonized regulatory framework. Furthermore, disparities in global regulatory landscapes have resulted in scarce reference data regarding long-term toxicity standards, which has impeded the clinical translation of platinum-based therapeutics, keeping it at a relatively slow pace. Since 1978, when the U.S. FDA approved cisplatin for the treatment of various solid tumors, it has remained the most successful platinum-based drug to date [315]. However, as a first-generation platinum chemotherapeutic, cisplatin, while effective in many cases, still exhibits significant off-target toxicity [317]. Particularly in the field of anticancer therapy, there is a growing clinical and pharmaceutical demand for new treatment regimens or advances in platinum-based drug therapy. Therefore, we briefly summarize the latest progress on platinum-based drugs that have been approved or are undergoing clinical translation here (Table S2).

Nevertheless, it is irrefutable that Pt nanozymes with redox-regulatory functions are becoming pivotal in the field of nanomedicine. The following points still need to be grasped in the future application of Pt nanozymes in biomedicine:

1. The formulation of a logical design strategy for the correlation between atomic structure and activity. The study of Pt nanozymes should not be limited to the straightforward assessment of enzyme activity through the arduous process of trial and error, which often necessitates determining whether the nanozymes possess a specific enzyme activity. More explicit, rational, and rapid design tools must be employed in the preparation and validation of the activity of the nanozymes. For instance, high-throughput screening, the utilization of big data for the analysis of existing data and the construction of libraries, machine learning-assisted synthesis of Pt nanozymes, the prediction of the corresponding activity through AI, and the subsequent in situ characterization to elucidate the conformational relationship between the atomic structure and the enzyme activity, as well as the establishment of a more universally general evaluation criterion for assessing the enzyme activity, are all potential avenues of enquiry. Furthermore, it is important to note that high catalytic activity does not necessarily correlate with high therapeutic efficacy or greater potency. It is important to note that while scavenging ROS can assist the body in resisting the inflammatory depletion caused by oxidative stress, excessive scavenging of ROS can also be detrimental. ROS is a vital signaling factor for life, and therefore, its overproduction or depletion can have adverse effects.

2. The implementation of an appropriate surface modification. In order to better tailor the next generation of Pt nanozymes, it may be necessary for us to perform appropriate surface modifications to improve the selectivity and stability of Pt nanozymes under physiological conditions, with the aim of reducing off-targeting with proteins or cellular components. Furthermore, functionalized modifications can facilitate the specific localization of Pt nanozymes to subcellular organelles, which is crucial for in vivo applications.

Furthermore, it is imperative that nanozymes are not confined to the laboratory setting for proof-of-concept purposes. Instead, there is a need to expedite the translation of these findings into tangible applications across a range of fields, including food, pollutant degradation, and communication security. It is therefore evident that further research is required in order to better tailor the next generation of Pt nanozymes.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

Jiajie Liu: Writing-review & editing, Writing-original draft. Long Zhao: Writing-review & editing, Writing-original draft. Jiani Xie: Writing-review & editing. Chuan Zhang: Writing-review & editing. Yuling Li: Writing-review & editing. Guobo Du: Writing-review & editing. Jiayan Zhang: Writing-review & editing. Yalan Wang: Writing-review & editing. Yanlan Xie: Writing-review & editing. Kun Guo: Writing-review & editing, Funding acquisition, Conceptualization. Wencheng Wu: Writing-review & editing, Funding acquisition, Conceptualization. Yuan Yong: Writing-review & editing, Funding acquisition, Conceptualization.

Funding

This work financially supported by the National Natural Science Foundation of China (52273304, 52573350, 52402353), Outstanding Youth Project of the Natural Science Foundation of Sichuan Province (2025NSFJQ0061), Sichuan Science and Technology Program (2025ZNSFSC0237), Young Elite Scientists Sponsorship Program by CAST (YESS) (2022-2024QNRC003), Innovative Team Project of Research and Development Plan of the Affiliated Hospital of North Sichuan Medical College (2025CX002), Research and Development Project of Affiliated Hospital of North Sichuan Medical College (2023-2ZD004, 2024PTZK003, 2024PTZK001), WeiZhou TeamFunds, Southwest Minzu University (SMUWZ202414).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This article is a review of the existing literature and does not report any original studies with human or animal subjects. Therefore, ethical approval was not required for this work. Additionally, all figures and illustrations included in this review have been properly credited and are used with appropriate permissions or under the terms of the applicable licenses. All included figures are properly licensed or permitted for reuse.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Declarations

The authors utilized Al-assisted editing tool (Grammarly) solely for language refinement purposes, including grammar checking, sentence structure optimization, and vocabulary enhancement. All conceptual development, technical content, and critical analysis remain entirely human-generated. The authors take full responsibility for the accuracy of information and academic integrity of this work.