Nanozymes at the Bio‐Nano Interface: From Synthesis, Defect Engineering, Catalytic Behavior in Biological Microenvironments, and Biosafety Implications

ABSTRACT The tunable catalytic behavior, structural robustness, and multifunctionality of nanozymes (NZs) enable them to emulate natural enzymatic activities under physiological conditions, positioning them as powerful platforms for advanced biomedical applications. This review provides a comprehensive overview of recent advances in NZs, with a particular emphasis on their synthesis strategies, and structure–activity relationships at the bio–nano interface. We critically analyze how chemical composition, atomic coordination, defect engineering, morphology, and surface chemistry govern catalytic performance, selectivity, and stability within complex biological microenvironments. Special attention is devoted to single‐atom and defect‐engineered NZs, highlighting rational design principles that enhance catalytic efficiency while minimizing undesired biological effects. Conventional and emerging green synthesis routes are evaluated for scalability, reproducibility, and translational feasibility. Furthermore, the therapeutic and diagnostic potential of NZs is discussed across antimicrobial, anti‐inflammatory, cancer, neurodegenerative, and wound‐healing applications. Finally, biosafety implications are systematically addressed, focusing on ion release, cytotoxicity, immunogenicity, and degradation pathways as key parameters for safe‐by‐design development. By integrating catalytic behavior with biological response and safety considerations, this review aims to provide a unified framework to guide the future design and clinical translation of nanozyme‐based biomedical systems.