A Whole‐Course‐Repair System Based on Neurogenesis‐Angiogenesis Crosstalk and Macrophage Reprogramming Promotes Diabetic Wound Healing

Diabetic wound (DW) therapy is currently a big challenge in medicine and strategies to enhance neurogenesis and angiogenesis have appeared to be a promising direction. However, the current treatments have failed to coordinate neurogenesis and angiogenesis simultaneously, leading to an increased disability rate caused by DWs. Herein, a whole‐course‐repair system is introduced by a hydrogel to concurrently achieve a mutually supportive cycle of neurogenesis‐angiogenesis under a favorable immune‐microenvironment. This hydrogel can first be one‐step packaged in a syringe for later in situ local injections to cover wounds long‐termly for accelerated wound healing via the synergistic effect of magnesium ions (Mg2+) and engineered small extracellular vesicles (sEVs). The self‐healing and bio‐adhesive properties of the hydrogel make it an ideal physical barrier for DWs. At the inflammation stage, the formulation can recruit bone marrow‐derived mesenchymal stem cells to the wound sites and stimulate them toward neurogenic differentiation, while providing a favorable immune microenvironment via macrophage reprogramming. At the proliferation stage of wound repair, robust angiogenesis occurs by the synergistic effect of the newly differentiated neural cells and the released Mg2+, allowing a regenerative neurogenesis‐angiogenesis cycle to take place at the wound site. This whole‐course‐repair system provides a novel platform for combined DW therapy. Combined neurogenesis‐angiogenesis crosstalk and macrophage reprogramming can pave way for the next generation of regenerative hydrogels to accelerate the recovery of chronic wounds. The work presents a novel approach to deliver drug‐loaded extracellular vesicles and magnesium ions by an in situ injectable hydrogel for concurrent supportive cycles of neurogenesis‐angiogenesis under a favorable immune‐microenvironment to heal diabetic wounds.