ROS-responsive phenylboronic acid-modified hyaluronic acid-loaded TA-siRNA nanogels accelerate diabetic wound healing

The impaired healing of diabetic wounds is primarily attributed to oxidative stress, which disrupts M2 macrophage polarization and dysregulates the inflammation-to-repair transition. To address this dysregulation, a reactive oxygen species (ROS)-responsive hydrogel was engineered by conjugating 3-aminophenylboronic acid with hyaluronic acid (HP) for the delivery of tannic acid-complexed siRNA nanogels (designated H-P/T@siRNA). The developed system demonstrated favorable tissue adhesion, self-healing properties, and efficient ROS-scavenging capacity. In vitro evaluations revealed that the platform significantly attenuated oxidative stress, effectively promoted macrophage repolarization toward an M2 phenotype, and enhanced endothelial cell migration and tubulogenesis. In a diabetic wound model, treatment with H-P/T@siRNA accelerated wound closure, achieving 82.16% healing by day 14, accompanied by marked downregulation of pro-inflammatory cytokines, enhanced collagen deposition, and increased neovascularization. Transcriptomic analysis elucidated that the observed therapeutic effects were mediated through remodeling of mitochondrial oxidative phosphorylation and core energy metabolism pathways, thereby driving the transition from inflammation to proliferation and remodeling. Collectively, this study demonstrates an immunomodulatory strategy employing an ROS-activated hydrogel for localized TNF-α siRNA delivery, which reshapes the wound microenvironment and facilitates diabetic wound repair.