Manganese-Based Polyoxometalate Nanozyme-Metformin Co-functionalized Hydrogel Promotes Diabetic Wound Regeneration by Enhancing Phagocyte Efferocytosis

Abstract

Efferocytosis, mediated by macrophages and dendritic cells (DCs), clears apoptotic cells to maintain tissue homeostasis, suppress inflammation, and promote repair. In diabetic wounds, hyperglycemia disrupts their efferocytic function, impeding healing progression. Therefore, restoring the efferocytic capacity of DCs and macrophages and establishing a dynamic "cyclic efferocytosis" between these 2 cell types are critical for diabetic wound regeneration. DCs are key drivers of cyclic efferocytosis because of their tissue-resident properties and glycogenolysis-driven energy supply. We postulated that targeted modulation of DCs was a promising strategy to establish this cycle. We developed GPP-M@L hydrogel, coencapsulating metformin (Met) and DC-targeted MnPOM nanozyme liposomes (Lipo-Dcpep@MnPOM). Met improved the high-glucose microenvironment. Lipo-Dcpep@MnPOM restored DC efferocytosis by enhancing mitochondrial adenosine triphosphate production. Treated DCs activated macrophage phosphatidylinositol 3-kinase/Akt signaling via paracrine effects, reinstating macrophage efferocytosis and promoting M2 polarization. Macrophages reciprocally enhanced DC efferocytosis via Rap1 and mitochondrial oxidative phosphorylation (OXPHOS), establishing a self-sustaining "cyclic efferocytosis" loop. This process further promoted regeneration by regulating endothelial cells and fibroblasts. Efficacy was confirmed in vitro and in diabetic rat models. In conclusion, by establishing a dynamic cyclic efferocytosis process using GPP-M@L, this study, grounded in the regulatory framework of "hyperglycemia-impaired immune homeostasis-efferocytosis cycle", provides a novel therapeutic paradigm for healing diabetic wounds and other immune homeostasis-related diseases.

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