A Self‐Cascading Immunomodulatory Hydrogel for Remodeling Infected Diabetic Wounds

ABSTRACT Methicillin‐resistant Staphylococcus aureus (MRSA)‐infected diabetic foot ulcers (DFUs) remain refractory to healing owing to persistent inflammation, hyperglycemia, and impaired tissue regeneration. Current antimicrobial strategies primarily eliminate viable bacteria but overlook pathogen‐associated molecular patterns (PAMPs) released upon bacterial death, which sustain NF‐κB/NLRP3 activation and prevent immune resolution. However, suppressing microbial burden without neutralizing PAMP‐driven inflammation fails to restore the regenerative wound microenvironment. Here, we report a self‐cascading hypoglycemic immunomodulatory hydrogel integrating Fe 3 O 4 @Au nanozymes with phenylboronic acid‐modified hyaluronic acid and dopamine‐functionalized silk fibroin. The platform exploits endogenous glucose to drive cascade catalysis for efficient MRSA eradication (∼99.99% with near‐infrared assistance), while dynamically exposing catechol and boronic acid motifs to sequester PAMPs and suppress inflammatory signaling. Consequently, macrophages are reprogrammed from pro‐inflammatory M1 to pro‐healing M2 phenotypes, enabling immune microenvironment remodeling. In MRSA‐infected DFU models, this coordinated antibacterial‐immunomodulatory strategy markedly accelerates wound closure, leaving only ∼13.97% residual area after 14 days. These results establish a design paradigm that couples biocatalysis with immune regulation for treating complex infected wounds.