Single-atom nanozymes in nanomedicine: catalytic precision, mechanistic insights, and translational opportunities.

Nanozymes, engineered by integrating enzymatic catalytic properties into nanomaterials, hold significant potential for biomedical applications. However, achieving high catalytic efficiency and substrate selectivity remains challenging. Single-atom nanozymes (SANs), featuring well-defined metal-ligand coordination environments and high atomic utilization efficiency, may provide catalytic advantages over conventional nanoparticles in specific reaction systems and under defined structural and operating conditions. While previous reviews have provided comprehensive overviews, a systematic analysis of the structure-activity relationships that govern SANs' performance in biological environments is still lacking. This review fills this gap by focusing on the atomic-level engineering strategies including coordination environment modulation, spatial configuration control, dual-atom sites, and emerging non-metal systems that have advanced the field since 2022. We critically compare the catalytic performance of SANs with that of nanoparticles and nanoclusters, clarifying the scope and limitations of the size-performance relationship in biocatalysis. Biomedical applications including antimicrobial therapy, cancer treatment, biosensing, and oxidative-stress protection are examined through the lens of catalytic mechanisms, with particular attention to how structural features translate into biological outcomes. The translational landscape is critically assessed, identifying both the opportunities and the barriers that must be overcome for clinical implementation. By integrating mechanistic insights with engineering principles, this Review provides a conceptual framework for the rational design of next-generation SANs.