Activating the cellular scavenger: A bioactive hydrogel promotes diabetic wounds via plant exosome-like nanovesicles enhanced macrophage efferocytosis.

Abstract

The core pathological process of impaired diabetic wound healing is closely associated with macrophage homeostasis imbalance and defective efferocytosis. To address this clinical challenge, this study innovatively developed a synergistic therapeutic system combining grape exosome-like nanovesicles (G-ELNs) and decellularized small intestinal submucosa matrix-modified hydrogel (SM). In vitro experiments demonstrated that G-ELNs effectively induced macrophage polarization toward the M2c phenotype and significantly enhanced efferocytosis efficiency by activating the c-Mer Tyrosine Kinase (MERTK) receptor. The SM hydrogel, with its triple-microporous topological structure and dynamic sustained-release properties, provided a long-term localized delivery platform for G-ELNs. In a diabetic rat full-thickness skin defect model, this system exhibited dual regulatory effects: spatially and temporally targeted delivery of exosomes promoted M2c macrophage polarization during the early inflammatory phase, rapidly clearing apoptotic cell debris through enhanced efferocytosis to block inflammatory cascades and transition the healing process to the proliferative phase, while simultaneously accelerating collagen fiber cross-linking and vascular network maturation in the proliferative phase, ultimately expediting wound closure. This study not only elucidates a novel immunomodulatory mechanism based on natural products but also proposes a clinically transformative strategy for efficient diabetic wound management.