A Hydrogen Sulfide-Releasing Dynamic Hydrogel Modulates Coordinated Neurovascular, Immune, and Angiogenic Responses...

Diabetic wound healing is impaired by a pathological microenvironment involving immune dysregulation, deficient angiogenesis, and compromised neural repair. Here, we engineered a dynamic phenylboronate ester-crosslinked hyaluronic acid/poly(vinyl alcohol) (HA/PVA) hydrogel for spatiotemporally controlled delivery of a novel hydrogen sulfide (H₂S) donor. In diabetic models, this hydrogel functions as both a reactive oxygen species (ROS) scavenger and an immunomodulatory platform. Sustained H₂S release promotes macrophage polarization toward the pro-reparative M2 phenotype, enhances angiogenesis through activation of the vascular endothelial growth factor (VEGF) signaling pathway, and facilitates sensory nerve repair by restoring calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) levels. Transcriptomic analysis further reveals that H₂S regulates gene networks associated with antioxidant defense, immune modulation, angiogenesis, and neuroprotection. In a diabetic rabbit ear model, this treatment markedly accelerates wound closure and suppresses hypertrophic scar formation by regulating collagen deposition and remodeling. Mechanistically, H₂S inhibits fibrosis through suppression of the transforming growth factor-β (TGF-β)/Smad signaling pathway. Collectively, this work presents an integrated therapeutic strategy that coordinates immune, vascular, and neural repair processes, offering a promising approach for diabetic wound regeneration and scar mitigation.