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

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. Scheme 1. Graphical Abstract. Schematic Illustration of the Synergistic Therapeutic System for Diabetic Wound Repair. The schematic diagram illustrates the synergistic therapeutic mechanism of G-ELNs and SM in diabetic wound repair. G-ELNs specifically activate the MERTK receptor on macrophages, inducing their polarization toward the reparative M2c phenotype and enhancing efferocytosis to clear apoptotic cell debris and block inflammatory cascades. Meanwhile, SM hydrogel utilizes its three-dimensional porous topological structure and dynamic sustained-release properties to achieve targeted delivery and prolonged release of G-ELNs, while promoting fibroblast/endothelial cell proliferation to fuel wound regeneration. In diabetic wounds, this system exerts dual regulatory effects: phenotypically, it reshapes the anti-inflammatory microenvironment by driving macrophage M2c polarization and secretion of pro-repair factors (e.g., IL-10, TGF-β); functionally, it amplifies efferocytosis through the MERTK signaling pathway, efficiently eliminating apoptotic fragments to disrupt the “inflammation-apoptosis-necrosis” vicious cycle. This coordinated action ultimately promotes ordered collagen fiber crosslinking and vascular network maturation, accelerating tissue regeneration. • Innovative System Design : SM@G-ELNs integrates grape exosome-like nanovesicles (G-ELNs) with modified hydrogel (SM), leveraging G-ELNs' immunomodulatory functions and hydrogel's sustained release for localized long-term delivery adapted to wound microenvironment. • Novel Mechanistic Insight : First evidence shows G-ELNs activate macrophage MERTK receptor to drive M2c repolarization and enhance efferocytosis, interrupting diabetic wound "inflammation-necrosis" cycle. • Translational Pathway Advancement : G-ELNs exploit plant-derived nanovesicles' abundant sources, low cost, and scalable production to bypass stem cell exosomes' culture complexity and translational barriers. In summary, the SM@G-ELNs system with its well-defined mechanism, high biocompatibility, and clinical accessibility provides an innovative, practical, and translatable strategy for diabetic ulcer treatment, significantly expanding the potential of plant-derived nanovesicles in chronic wound repair.