Microenvironment-Responsive Polyaniline− Gelatin Conductive Hydrogel Promotes Infected Diabetic Wound Healing by Modulating Skin-Resident Cells Behavior

Abstract Diabetic wound healing is severely impaired by persistent inflammation, bacterial infection, impaired angiogenesis, and especially disrupted bioelectrical signaling. Conductive hydrogels can help restore local bioelectrical signal transmission and provide an attractive strategy for intractable wound healing by modulating the behaviors of bioelectrically responsive skin-resident cells. Here, we developed a glucose/pH-responsive polyaniline− gelatin conductive hydrogel (HGP@D) based on double dynamic covalent crosslinking of the imine bond and boronic ester bond for promoting the Staphylococcus aureus-infected full-thickness diabetic wound healing. The HGP@D hydrogel had strong mechanical property, great tissue adhesive strength, glucose/pH dual-responsive drug release behavior, alongside robust broad-spectrum antibacterial activity, and potent intracellular antioxidation. The HGP@D hydrogel restored local bioelectrical signaling and created an anti-inflammatory wound microenvironment, thereby modulating the behaviors of skin-resident cells involved in diabetic wound repair, including fibroblast migration, macrophage M2-like polarization, and endothelial angiogenic activity. Mechanistic analyses suggested that the HGP@D hydrogel promoted infected diabetic wound healing through two Ca2+-associated regulatory axes: the Ca2+/CaMKKβ/AMPK/NF-κB axis for inflammatory regulation and the Ca2+/PI3K/Akt/mTOR/HIF-1α/VEGF axis for angiogenesis and tissue reconstruction. Overall, HGP@D provides a promising clinical therapeutic strategy for the advanced healing of diabetic wounds and other non-healing wounds by integrating glucose/pH-responsive microenvironment regulation with bioelectrical modulation.