Single‐Atom Enzymes: From Evolutionary Insights, Precision Engineering to Breakthroughs in Biomedical Applications

Abstract Single‐atom enzymes (SAEs), integrating the catalytic efficiency of single‐atom catalysts with enzymatic functions, represent a paradigm shift in biomedicine. Comprising natural enzymes, mimic enzymes, and single‐atom nanozymes, SAEs leverage isolated metal atoms as catalytic centers. Natural enzymes, evolved over billions of years, feature monoatomic active sites for precise biocatalysis under physiological conditions. Mimic enzymes (e.g., DNAzymes) represent a biomimetic adaptation, replicating natural active sites via programmable molecular scaffolds to enhance stability while inheriting an evolutionary bias that prioritizes structural robustness over catalytic diversity, limiting multifunctionality. In contrast, nanozymes embody an evolutionary leap: they sacrifice partial biocompatibility to achieve multienzyme‐mimicking capabilities and scalable production through inorganic nanomaterial engineering, thereby expanding the catalytic landscape beyond biological boundaries, though this advancement introduces concomitant immunogenicity challenges. This review systematically examines cutting‐edge advances in SAE applications across biomedical domains including biosensing, oncotherapy, antimicrobial strategies, and oxidative stress management. This review particularly presents a critical analysis of current challenges and emerging opportunities, proposing rational design principles for next‐generation SAEs with enhanced multifunctionality. By elucidating fundamental design strategies and translational potential, this work aims to accelerate the development of precision catalytic platforms for modern biomedicine.