A Hydrogen Sulfide–Releasing Dynamic Hydrogel Modulates Coordinated Neurovascular, Immune, and Angiogenic Responses for Scar‐Suppressed Diabetic Wound Repair

ABSTRACT

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 (H ₂ S) donor. In diabetic models, this hydrogel functions as both a reactive oxygen species (ROS) scavenger and an immunomodulatory platform. Sustained H ₂ S 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 H ₂ S 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, H ₂ S 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.