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

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 (Cu²⁺), 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.