A pH/ROS dual-responsive hydrogel promotes diabetic wound healing by controlled release of O2 and EGCG to induce angiogenesis and immunomodulation

Diabetic wounds are marked by persistent infection, hypoxia, excessive reactive oxygen species (ROS), and impaired angiogenesis, which present significant challenges for clinical management. In this study, a pH/ROS dual-responsive multifunctional hydrogel (QOF-EGCG/Hb@PDA) was constructed by grafting 3-carboxyl-4-ffuorophenylboronic acid (FPBA) onto Quaternary ammonium chitosan (QCS) to form Schiff base bonds with Oxidized gellan gum (OGG) (pH response), and by reacting FPBA with Epigallocatechin gallate (EGCG) to form borate bonds (ROS response). Hb@PDA nanoparticles were then loaded into the hydrogel. Under acidic conditions, the cleavage of Schiff base bonds triggers the release of Hb@PDA, providing sustained oxygen delivery to alleviate hypoxia. Additionally, in ROS-rich environments, the cleavage of borate ester bonds promotes EGCG release, exerting antioxidant and anti-inflammatory effects. QOF-EGCG/Hb@PDA displays excellent self-healing capacity and tissue adhesion, as well as remarkable photothermal activity. Furthermore, it demonstrates excellent antibacterial, antioxidant, anti-inflammatory, pro-angiogenic, and hemostatic properties. In vivo studies confirmed that this hydrogel markedly accelerated diabetic wound healing by enhancing epithelial regeneration, promoting collagen deposition, regulating inflammatory responses, and facilitating angiogenesis. Transcriptomic analysis revealed that the hydrogel promotes angiogenesis by activating the HIF-1α/VEGF signaling pathway, which plays a pivotal role in vascular formation and tissue regeneration, thereby accelerating the healing of diabetic wounds. Collectively, QOF-EGCG/Hb@PDA provides a promising and comprehensive strategy with great potential for application in diabetic wound treatment.