A Self-Cascading Immunomodulatory Hydrogel for Remodeling Infected Diabetic Wounds

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 Fe₃O₄@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.