Mitochondrion-targeted therapies for diabetic wound healing: from mechanism to therapeutic opportunity

Diabetic wounds are a major clinical challenge. They are driven by persistent hyperglycemia and chronic inflammation that synergistically disrupt mitochondrial homeostasis, manifesting as impaired bioenergetics, excessive reactive oxygen species (ROS) accumulation, and dysregulated mitochondrial quality control. Mitochondrial dysfunction critically undermines cellular proliferation, angiogenesis, and immunomodulation, which are essential for effective tissue repair. Intercellular mitochondrial transfer, mediated through tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junctions (GJs), and cell fusion, has recently emerged as a biologically compelling endogenous rescue mechanism capable of restoring bioenergetic capacity and redox homeostasis in metabolically compromised recipient cells. In this review, we systematically examine the mechanistic basis of mitochondrial dysfunction in the diabetic wound microenvironment, critically evaluate the therapeutic potential of intercellular mitochondrial transfer, and propose an integrated mechanism-to-translational framework coupling transfer-based strategies with bioresponsive and mitochondrion-targeted biomaterials tailored to the pathological wound milieu. Furthermore, we identify key translational barriers-including insufficient protocol standardization, the absence of robust characterization criteria, and a lack of quantitative benchmarks for transfer efficacy-that must be addressed to advance these strategies toward clinical application, thereby offering a conceptual foundation and translational roadmap for mitochondrion-centered regenerative approaches in diabetic wound care.