Reprogramming endothelial tip cell fate via PI3K-VEGF signaling cascade: a multifunctional adhesive hydrogel for enhanced angiogenesis and infected wound healing

Infected skin wounds represent a significant healthcare challenge, affecting millions of patients worldwide and imposing substantial economic burden on healthcare systems. Traditional wound dressings and systemic antibiotics face critical limitations including lack of tissue adhesion in wet environments, increasing antibiotic resistance, and inability to promote tissue regeneration, resulting in suboptimal healing outcomes. In this research, we formulated an injectable composite hydrogel comprising dopamine-modified sodium alginate, chondroitin sulfate, and silk fibroin as the primary matrix, with magnesium oxide (MgO) nanoparticles and human umbilical mesenchymal stem cells (hUMSCs)-derived exosomes (Exo) as functional components. The resultant ACS/MgO/Exo hydrogel exhibits effective tissue adhesion, superior hemostatic capability, mild-photothermal therapy (M-PTT)-mediated antibacterial activity, and enhanced angiogenesis. In vitro studies demonstrated that the hydrogel effectively reduced bleeding time, eliminated bacteria through M-PTT, and significantly enhanced endothelial tip cell activation, proliferation, motility, and vascularization through activation of the PI3K-AKT-NF-κB-VEGF signaling cascade. In vivo experiments with infected full-thickness defect model confirmed the composite hydrogel’s ability to accelerate wound closure, eliminate bacterial infection, enhance collagen deposition, and promote vascularization while simultaneously modulating the inflammatory response. This multifunctional hydrogel represents a promising therapeutic platform for complex infected wound management, addressing the critical clinical need for integrated solutions that simultaneously achieve adhesion, hemostasis, infection control, and tissue regeneration.