Self‐Adaptive Glycopeptide Hydrogel Reinforced With Hybrid Nanozymes for Orchestrating the Glucose Depletion‐Driven ROS‐H 2 S Signaling Toward Multistage Repair of Refractory Diabetic Wounds

Abstract

Chronic diabetic wounds, driven by persistent infection, oxidative stress, and hyperglycemia, remain demand dressings capable of staged, microenvironment‐adaptive regulation. Here, we develop a self‐adaptive glycopeptide hydrogel composite (MnS@ZGF Gel) reinforced with hybrid nanozymes to orchestrate a glucose depletion‐driven ROS‐H 2 S signaling cascade for multistage diabetic wound repair. The hybrid nanozyme (MnS@ZG) features a MnS core coated with Co 2+ /dimethylimidazole/glucose oxidase shell, enabling synergistic glucose depletion, ROS‐mediated antibacterial action, and sustained H 2 S‐driven anti‐inflammatory and pro‐angiogenic signaling. Embedded in a dynamic glycopeptide network formed by oxidized sodium alginate (OSA), ε‐poly‐L‐lysine (PL), and thermosensitive F127 via spontaneous self‐crosslinking, MnS@ZGF Gel exhibits excellent injectability, tissue adhesion, mechanical strength, and self‐healing, allowing conformal coverage over irregular wounds. Mechanistic simulations reveal that hydrogen bonding and metal coordination synergistically stabilize the nanozyme‐hydrogel interface. In vitro, MnS@ZGF Gel exhibits a temporally programmed therapeutic profile through a glucose‐responsive ROS‐H 2 S cascade, enabling early ROS‐mediated infection control followed by H 2 S‐driven immunomodulation and fibroblast migration. In vivo, transcriptomic and histological analyses demonstrate that it effectively remodels the wound immune microenvironment, accelerating wound closure, neovascularization, and collagen remodeling while minimizing scar formation and maintaining excellent biocompatibility. This work provides a promising strategy for the temporally programmed, multistage repair of refractory diabetic wounds with considerable clinical translational potential.