Innovative Strategies to Overcome Stability Challenges of Single-Atom Nanozymes

• 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.