Innovative Strategies to Overcome Stability Challenges of Single-Atom Nanozymes

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.