Iron Homeostasis Regulating Glycopeptide Hydrogel Reprograms the Healing Process of Diabetic Wounds Infected With MRSA

Abstract Optimal healing of diabetic chronic wound requires a well‐organized cascade integration of bacterial death, cell migration and proliferation, and extracellular remodeling. However, such biological progress is usually impaired in chronic diabetic wound and traditional antibacterial hydrogels unmatched for ordered repair needs. Herein, an iron‐coordinated glycopeptide hydrogel (Fe‐GP gel) that could effectively treat MRSA‐infected chronic diabetic wounds within 11 days by reprogramming healing process is developed. This Fe‐GP hydrogel is formed based on glucomannan‐decorated peptide nanofibers framework and then loaded with tannic acid/Fe nanocomplexes. The burst release of nanocomplexes is achieved to conduct the first healing stage, which could induce the ferroptosis‐like death of methicillin‐resistant Staphylococcus aureus (MRSA) for eliminating over 98% of MRSA bacteria by metabolism disrupting within 6 h. In the second healing stage, sustained release of glucomannan promotes M2 macrophage polarization (five times higher than control group) through extracellular signal‐regulated kinase and signal transducer and activator of transcription 6 (ERK/STAT6) pathway within 2 days. After the elimination of MRSA and restoration of immune microenvironment, the remaining 3D peptide nanofibers framework is able to facilitate extracellular remodeling through anchoring fibroblast cells as the third healing stage within weeks. Overall, this glycopeptide hydrogel has demonstrated a promising approach to realize the orderly progression during healing process for enhanced treatment of drug‐resistant bacteria‐infected chronic wounds.