Key Takeaways & Executive Findings
- •• This review uniquely provides an in-depth focus on the stability issues of single-atom nanozymes (SAzymes), covering multiple aspects such as metal atom clustering and active site loss, ligand bond breakage at high temperature, insufficient environment tolerance, biosecurity risks, and limited catalytic long-term stability. • This review integrates and systematically discusses a wide range of potential strategies to overcome stability issues, including synthesis process optimization (space-limited strategy, coordination site design, bimetallic synergistic strategy, defect engineering strategy, atom stripping-capture), surface modification, and dynamic responsive design. • To transform SAzymes from 'star materials' of the laboratory into precise clinical tools for medicine, the authors propose the four-dimensional roadmap: structure-predictable, activity-tunable, biocompatible, and scalable. • The review highlights the potential of SAzymes in biomedical applications such as disease diagnosis, antitumor therapy, antimicrobial therapy, and anti-oxidative stress therapy, while emphasizing the need for stability to achieve clinical translation.
Abstract
Single-atom nanozymes (SAzymes) exhibit exceptional catalytic efficiency due to their maximized atom utilization and precisely modulated metal-carrier interactions, which have attracted significant attention in the biomedical field. However, stability issues may impede the clinical translation of SAzymes. This review provides a comprehensive overview of the applications of SAzymes in various biomedical fields, including disease diagnosis (e.g., biosensors and diagnostic imaging), antitumor therapy (e.g., photothermal therapy, photodynamic therapy, sonodynamic therapy, and immunotherapy), antimicrobial therapy, and anti-oxidative stress therapy. More importantly, the existing challenges of SAzymes are discussed, such as metal atom clustering and active site loss, ligand bond breakage at high temperature, insufficient environment tolerance, biosecurity risks, and limited catalytic long-term stability. Finally, several innovative strategies to address these stability concerns are proposed—synthesis process optimization (space-limited strategy, coordination site design, bimetallic synergistic strategy, defect engineering strategy, atom stripping-capture), surface modification, and dynamic responsive design—that collectively pave the way for robust, clinically viable SAzymes.
1. Introduction
The field of nanozymes experienced a significant milestone in 2007 when Yan et al. first demonstrated that Fe3O4 nanoparticles exhibit natural horseradish peroxidase activity, a discovery that generated substantial scientific interest [1]. Building on this foundation, Wei and Wang provided a defining characterization in 2013, introducing nanozymes as 'a class of mimetic enzymes that combine the unique properties of nanomaterials with distinctive catalytic functions' [2]. In 2022, our research team established the first standardized development process for prussian blue nanozymes [3], and further elucidated the catalytic mechanism of Fe3O4 nanoparticles. Specifically, we revealed that Fe2+ ions within the Fe3O4 structure can regenerate surface Fe2+ through electron transfer mediated by the Fe2+–O–Fe3+ chain, enabling sustained POD-like catalytic activity. This cyclic process allows for continuous regeneration of surface Fe2+ ions, maintaining prolonged catalytic function [4].
To expand the practical applications of these findings, our research group collaborated with Xu to spearhead the development of China's inaugural international standard within ISO/TC229/WG3 published in 2023, the standard titled 'Nanotechnology-Methods for measuring peroxidase-like activity of metal and metal oxide nanoparticles' (ISO/TS 5094: 2023) provides critical methodology for evaluating nanozyme activity [5]. Collectively, these advancements have transformed the understanding of inorganic nanomaterials, moving beyond the traditional view of their biological inertness to reveal their intrinsic biological effects and novel properties. This paradigm shift has significantly broadened the scope of research in the field of mimetic enzymes, extending from organic complexes to inorganic nanomaterials, and has opened new avenues for innovative biomedical applications.
While traditional nanozymes offer significant benefit, such as high stability, low cost, large-scale production, designability, and multifunctional integration, they are still hindered by several critical limitations. These include a low density of active sites, insufficient electron transfer efficiency, and relatively low catalytic efficiency [6, 7]. The multilevel structural features of nanozymes result in a complex catalytic mechanism [8], making it challenging for conventional nanozymes to accurately replicate the intricate coordination structure of natural enzymes.
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Rong Guo, Qiuzheng Du, Yaping He, Haoan Wu, Yu Zhang, Ziwei Jing (2026). Innovative Strategies to Overcome Stability Challenges of Single-Atom Nanozymes. Nano-Micro Letters. https://doi.org/10.1007/s40820-025-01939-2
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Frequently Asked Questions
What are single-atom nanozymes (SAzymes)?
Single-atom nanozymes are nanomaterials that mimic enzyme activity, featuring isolated metal atoms dispersed on a support. They exhibit maximized atom utilization and precisely modulated metal-carrier interactions, leading to exceptional catalytic efficiency in biomedical applications.
What are the main stability challenges of SAzymes?
The main stability challenges include metal atom clustering and active site loss, ligand bond breakage at high temperatures, insufficient environment tolerance, biosecurity risks, and limited catalytic long-term stability.
What strategies are proposed to overcome stability issues?
Innovative strategies include synthesis process optimization (space-limited strategy, coordination site design, bimetallic synergistic strategy, defect engineering strategy, atom stripping-capture), surface modification, and dynamic responsive design.
What biomedical applications are discussed for SAzymes?
SAzymes are applied in disease diagnosis (biosensors and diagnostic imaging), antitumor therapy (photothermal, photodynamic, sonodynamic, and immunotherapy), antimicrobial therapy, and anti-oxidative stress therapy.
What is the proposed roadmap for clinical translation of SAzymes?
The authors propose a four-dimensional roadmap: structure-predictable, activity-tunable, biocompatible, and scalable, to transform SAzymes from laboratory 'star materials' into precise clinical tools.
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