Multifunctional Copper Ion‐Mediated Carrier‐Free Scutellarin Hydrogel for Diabetic Wound Healing

ABSTRACT Chronic diabetic wounds suffer from persistent inflammation, oxidative stress, and impaired angiogenesis. This study develops a carrier‐free Cu‐SCU hydrogel via self‐assembly of scutellarin (SCU) and copper ions (Cu 2 ⁺), without polymers or excipients. Spectroscopic analyses and molecular dynamics simulation confirm Cu‐SCU coordination, yielding an injectable hydrogel with mechanical integrity. In vitro, Cu‐SCU demonstrates excellent biocompatibility, potent ROS scavenging, and immunomodulation by polarizing macrophages to the reparative M2 phenotype. It also exhibits strong hemostatic activity, promoting RBC/platelet aggregation and accelerating coagulation in vitro and in vivo (liver hemorrhage and tail‐amputation models). In diabetic full‐thickness wounds, Cu‐SCU significantly accelerates healing, enhances re‐epithelialization, collagen deposition, and vascular maturation. Analyses reveal reduced neutrophilic infiltration, diminished pro‐inflammatory cytokines, and sustained M2 macrophage presence. Proteomic analysis and Western blot validation results demonstrated that it promotes angiogenesis by regulating the MAPK, cGMP‐PKG, VEGF, and HIF‐1 signaling pathways, as well as upregulating the expression of key pathway proteins including HIF‐1α, CDC42, and HK2. Cu‐SCU hydrogel promotes healing through multifaceted mechanisms: redox regulation, immune modulation, and pro‐angiogenic activation. This simple, biocompatible, and efficacious platform offers a promising alternative to carrier‐based systems for chronic wound therapy.