Bioinspired hierarchical delivery system with macrophage-like nanovesicles encapsulation for diabetic wound healing

•A hierarchical delivery system was developed for treating diabetic wounds.•NVs realized inflammatory cytokines neutralization and intracellular SIM delivery.•The hydrogel MPs could protect and release NVs in the oxidative stress environment.•The delivery system reduced inflammation and facilitated new tissue formation. Chronic hard-healing diabetic wounds constitute an immense health and economic burden on global health. Great efforts have been put to develop multifunctional drug delivery systems for improving wound healing. Here, inspired by the physiologically immunogenic response processes, we presented a novel hierarchically structured delivery system with macrophage-like nanovesicle (NV) encapsulation for promoted diabetic wound healing. The NVs were assembled by the fusion membranes of macrophage and synthetic lipid; while the hierarchically structured delivery system was constructed by encapsulating these NVs inside hydrogel microspheres (NV-MPs) using microfluidics. The hydrogel MPs could protect and release the encapsulated NVs in the oxidative stress environment of the diabetic wound. As the NVs possessed the ability of pro-inflammatory cytokine neutralization and intracellular delivery of their loaded simvastatin (SIM), the bioinspired hierarchically structured delivery system could greatly enhance the migration ability and tube formation of human umbilical vein endothelial cells (HUVECs). Based on these features, the practical performances of the resultant delivery system were demonstrated in full-thickness cutaneous wounds in type I diabetic rats, which exhibited desirable wound healing conditions by effectively reducing inflammation levels and facilitating blood vessel formation and collagen deposition in the wound tissues. Thus, we believe that the proposed bioinspired hierarchical delivery system would be an ideal carrier for treating wound healing and other tissue regeneration-related applications.