Sequence-Engineered Multifunctional Peptide Nanozyme Gel for Catalytic Microenvironment Regulation in Diabetic Infected Wounds

Abstract

Chronic diabetic wounds are characterized by persistent infection, redox imbalance, and dysregulated enzymatic activity, yet current biomaterials largely function as passive dressings, with limited capacity to actively intervene in the stalled healing cascade. Here, we report a sequence-programmed peptide nanozyme that encodes multiple enzyme-mimetic activities within a single supramolecular framework for adaptive microenvironment regulation. By mimicking the coordination motifs of natural hydrolases and superoxide dismutase, a de novo peptide sequence, C7-RD(S)HHEEH, was rationally engineered to encode integrated nitrogen/oxygen metal-binding sites. The incorporation of a side-chain–modified serine enhances coordination adaptability, while glutamate residues facilitate catalytic functionality. Upon Cu2+ coordination, the peptide self-assembles into a nanozyme exhibiting hydrolase (HYD)-, oxidase (OXD)-, peroxidase (POD)-, and superoxide dismutase (SOD)-like activities within a unified framework, thereby enabling coordinated regulation of enzymatic debridement, antibacterial defense, and redox homeostasis. Incorporated into a sprayable gelatin hydrogel, the nanozyme provides conformal wound coverage while maintaining excellent biocompatibility and sustained catalytic functionality. In a diabetic bacteria-infected wound model, the nanozyme gel significantly accelerates wound closure, enhances angiogenesis and collagen deposition, and restores tissue regeneration. Our work demonstrates that rational peptide sequence design can encode complex, multimodal catalysis into synthetic nanozymes, offering a programmable approach for active regulation of pathological microenvironments in chronic wound therapy.