ROS-responsive H2S-releasing cationic chitosan sponge integrating enhanced immunomodulation with angiogenesis for diabetic wound healing

Developing a diabetic wound dressing that integrates immunomodulation, angiogenesis, and anti-infection effects remains a challenge. Herein, we prepared a novel hydrogen sulfide (H 2 S) donor-modified quaternized chitosan sponge. The sponge enabled controlled H 2 S release in response to reactive oxygen species (ROS), decreasing intracellular ROS while increasing H 2 S levels. The sponge modulated Raw 264.7 macrophage polarization toward the M2 phenotype by inhibiting NF-κB activation, thereby reducing inflammatory cytokine expression and excessive inflammation. The sponge enhanced human umbilical vein endothelial cell migration and angiogenesis by upregulating the vascular endothelial growth factor and endothelial nitric oxide synthase expression. The sponge showed strong antibacterial activity against methicillin-resistant Staphylococcus aureus and Escherichia coli , reducing wound inflammatory responses. The biocompatible sponge accelerated diabetic wound healing by synergistically promoting re-epithelialization, collagen deposition, and angiogenesis, while attenuating inflammation, superior to commercial 3 M™ dressing. Our ROS-responsive H 2 S-releasing cationic chitosan sponge exhibits significant potential for advanced diabetic wound care.