AICAR-induced energy supply and paracrine activity of endothelial cells accelerate chronic diabetic wound healing by promoting angiogenesis and modulating macrophage reprogramming

Chronic diabetic wound healing is severely hampered by endothelial cell (EC) dysfunction, defective angiogenesis, and a persistent inflammatory microenvironment, yet the crosstalk between EC energy metabolism and macrophage polarization in this process remains poorly understood. Here, we identified an AMPK-dependent metabolic pathway in ECs that orchestrated both angiogenic restoration and macrophage immune reprogramming for diabetic wound repair, and translated this mechanism into a functional three-dimensional (3D) scaffold (MEWs+GelMA@AI) fabricated by melt electrospinning writing technology. Acadesine (AICAR) efficiently induced a high-energy state in ECs by activating AMPK, preserving mitochondrial ultrastructure, enhancing respiratory-chain complex activity, and increasing VEGF expression and angiogenic potential. Notably, we discovered that AI-EXO, secreted by these metabolically activated ECs, delivered GAS6 to macrophages as a key paracrine factor, thereby triggering activation of the MER/AKT pathway and driving M1-to-M2 polarization. To our knowledge, this is the first report identifying exosomal GAS6 as a mediator of EC-macrophage crosstalk in diabetic wound healing. The MEWs+GelMA@AI scaffold, characterized by a porous structure and sustained AICAR release, exhibited excellent cytocompatibility and proangiogenic activity in vitro . In vivo , the scaffold significantly accelerated diabetic wound closure by promoting neovascularization, reducing inflammatory infiltration, and increasing the M2/M1 macrophage ratio, without detectable systemic toxicity in major organs. These findings establish a critical link between EC energy metabolism and immune microenvironment remodeling, providing a potentially translatable metabolic-engineering strategy for chronic diabetic wounds. This study opens new avenues for regenerative therapies targeting metabolic-immune interactions.