Therapeutic mitochondrial transfer via mesenchymal stem cell-derived microvesicles for macrophage modulation in myocardial infarction complicated by diabetes.

Diabetes is closely associated with the onset and prognosis of myocardial infarction (MI). However, current treatment strategies primarily focus on addressing MI, often neglecting the detrimental effects of hyperglycemia, a hallmark of diabetes. Hyperglycemia disrupts the crucial transition of macrophages from the M1 to M2 phenotype, thereby exacerbating MI-induced tissue damage and impeding myocardial repair. Mitochondria have emerged as key regulators of macrophage phenotype, suggesting the potential for modulating macrophages through mitochondria transfer. In this study, we developed microvesicles containing active mitochondria (Mito@euMVs), derived from enucleated mesenchymal stem cells. We found that 71.7 % of the Mito@euMVs contained mitochondria, with no nuclear material present. Mito@euMVs effectively delivered mitochondria into macrophages, facilitating their transit from M1 to M2 phenotype, even in hyperglycemia. Further in vivo study using a diabetic rat model of MI confirmed their cardiac repair properties. Treatment of Mito@euMVs led to 24.55 ± 4.33 % improvement in ejection fraction and 15.48 ± 4.04 % in fractional shortening 28 days post-MI in diabetic rats. Additionally, Mito@euMVs mitigated infarcted left ventricular wall thinning and fibrosis, enhanced M2 macrophage phenotype, promoted cardiomyocyte survival. Our study emphasizes the effective modulation of macrophage phenotype via mitochondrial transfer with Mito@euMVs and highlights their promising potential in treating MI.