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Impaired wound healing in diabetes is closely related to the imbalance of macrophage homeostasis and the dysfunction of phagocytosis. In this study, a synergistic treatment system was developed, combining exosome nanovesicles derived from grapes with modified hydrogels of decellularized submucosa of small intestinal mucosa. In vitro experiments demonstrated that G-ELNs induced macrophage polarization to the M2c phenotype by activating the MERTK receptor and significantly enhanced the efficiency of phagocytosis. The SM hydrogel has a three-layer microporous topological structure and continuous release properties, providing a long-term local delivery platform for G-ELNs. In a diabetic rat model of full-thickness skin defect, this system achieved spatial and temporal targeted delivery, promoting early M2c polarization and clearance of apoptotic cells, blocking the inflammatory cascade, accelerating collagen cross-linking and vascular maturation, and ultimately accelerating wound closure. This study elucidates a new mechanism of immune regulation from natural product sources.
Research Highlights
This study for the first time combined exosomes derived from grapes with decellularized submucosa hydrogels of small intestine mucosa to construct a synergistic treatment system, precisely targeting the two core pathological links of macrophage homeostasis imbalance and dysfunction of phagocytosis in diabetic wounds. G-ELNs induced M2c polarization and enhanced phagocytosis through the MERTK pathway, and the SM hydrogel provided continuous local delivery, jointly achieving temporal and sequential regulation from early inflammatory clearance to the proliferative stage of vascular maturation. Innovation Points
① Application of natural exosomes: The first time, exosomes derived from grapes were utilized to regulate macrophage polarization and autophagy;
② Dual-module collaborative design: The functional integration of exosome active components and micro-structured hydrogel carriers;
③ Whole-process temporal regulation: Achieving multi-stage healing intervention from inflammation clearance to tissue remodeling.
Material development
1 Materials
A synergistic therapeutic system composed of exosome nanovesicles derived from grapes and modified hydrogel of decellularized submucosa of small intestinal mucosa.
2 Function
This hydrogel achieves temporal regulation of inflammation clearance and tissue remodeling by continuously local delivery of G-ELNs, activating the MERTK pathway to induce M2c polarization and enhance autophagy.
Thought extension
This work provides a new idea for dual-target intervention of immune and autophagy in chronic diabetic wounds. In the future, the functional differences of exosomes from different plant sources, optimization of hydrogel microstructure parameters, and the regulatory mechanism of autophagy can be explored for their universal application in other inflammatory disease models, further promoting the transformation of regenerative medicine from "single anti-inflammatory" to "immune clearance - tissue remodeling collaborative programming".
Original source
Bioactive Materials (IF 20.3) Pub Date : 2026-03-24,
DOI: 10.1016/j.bioactmat.2026.03.039 Yue-Qi Zhang, Rong Nie, Zi-Yuan Feng, Ming-Hui Fan, Zhi-Xue Shen, Xiu-Zhen Zhang, Ji-Ye Zhang, Yan-Lin Jiang, Qing-Yi Zhang, Kai Huang, Li-Ping Mou, Yan-Ming Chen, Hui-Qi Xie
