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Single-atom nanozymes (SAzymes), featuring atomically dispersed active sites with well-defined coordination environments, have emerged as a powerful nanoplatform for mimicking metalloenzyme activity with high catalytic precision. However, their broader biomedical application remains limited by insufficient understanding of structure-function relationships and challenges in clinical translation. Here, we establish a structure-activity-property relationship (SAPR) framework to bridge atomic-level design with catalytic behavior and biomedical function. We first outline the fundamental principles for constructing single-atom active sites, followed by SAzyme-specific design strategies, including coordination environment modulation, electronic structure modulation, defect engineering, and multi-atom site construction. We then highlight how these atomic-level features govern key catalytic processes, i.e., reactive oxygen species (ROS) generation, reaction kinetics, as well as selectivity. Building on this framework, we discuss structure-driven biomedical applications of SAzymes in biosensing and catalytic therapy. Atomically defined active sites enable enhanced signal amplification, sensitivity, and reproducibility in biosensing, while in therapeutic applications, SAzymes regulate biological systems through ROS-mediated catalysis, microenvironment and metabolic modulation, and energy-assisted processes to address challenges such as tumor hypoxia, redox imbalance, and inflammation storms. Finally, key challenges, including stability in complex biological environments, protein corona effects, scalability, and biosafety, are critically discussed. This review provides a unified mechanistic perspective for the rational design and clinical translation of next-generation SAzyme-based nanomedicines.
Chong et al. (Sat,) studied this question.