Bioinspired nanovesicles released from injectable hydrogels facilitate diabetic wound healing by regulating macrophage polarization and endothelial cell dysfunction

Wound healing is one of the major global health concerns in diabetic patients. Overactivation of proinflammatory M1 macrophages could lead to delayed wound healing in diabetes. 4-octyl itaconate (4OI), a derivative of the metabolite itaconate, has aroused growing interest recently on account of its excellent anti-inflammatory properties. Cell membrane coating is widely regarded as a novel biomimetic strategy to deliver drugs and inherit properties derived from source cells for biomedical applications. Herein, we fused induced pluripotent stem cell-derived endothelial cell (iEC) membrane together with M1 type macrophage membrane to construct a hybrid membrane (iEC-M) camouflaged 4OI nanovesicles (4OI@iEC-M). Furthermore, bioinspired nanovesicles 4OI@iEC-M are incorporated into the injectable, multifunctional gelatin methacryloyl hydrogels for diabetic wound repair and regeneration. In our study, bioinspired nanovesicles could achieve dual-targeted deliver of 4OI into both M1 macrophages and endothelial cells, thereby promoting macrophage polarization and protecting endothelial cells. With the synergistically anti-inflammatory and immunoregulative effects, the bioinspired nanovesicles-loaded hydrogels could facilitate neovascularization and exhibit superior diabetic wound repair and regeneration. Taken together, this study might provide a novel strategy to facilitate diabetic wound healing, thereby reducing limb amputation and mortality of diabetes.

4-octyl itaconate; Bioinspired nanovesicles; Diabetic wound healing; Macrophage polarization; Neovascularization.