Biomimetic Metallopeptidases for Biomedical Applications: From Modular Design to Disease Treatment

ABSTRACT Biomimetic metallopeptidases, as an emerging class of artificial enzyme systems, have demonstrated tremendous application potential in the biomedical field in recent years. Their core design principle is to rationally control amino acid composition and three‐dimensional conformation so that programmable peptide sequences can efficiently coordinate metal ions and thereby drive hierarchical self‐assembly into supramolecular architectures. The incorporation of rare metal elements can further confer distinctive advantages in catalytic activity, resistance to inactivation, and functional diversity that are difficult to achieve with conventional enzymes. This review summarizes current principles of sequence design, synthetic strategies, metal coordination chemistry, and multiscale assembly mechanisms. It further highlights the distinctions between in vitro and in vivo self‐assembly, along with their respective advantages. Concurrently, we further discuss their therapeutic and diagnostic potentials in cancer therapy, immune modulation, antimicrobial protection, wound healing, and early disease detection. Looking forward, convergence with AI‐guided sequence optimization, bio‐orthogonal metal‐linking strategies, and multimodal synergistic interventions, together with the development of biodegradable and biocompatible platforms, holds promise for accelerating translation. Overall, bioinspired metallopeptidases provide a versatile and programmable nanomedicine framework that unites catalytic functionality with spatiotemporal control, charting a compelling path toward precision diagnostics and personalized therapy.