Engineered miR-122 inhibitors preserve endothelial mitochondrial function and prevent vascular dysfunction in obesity-associated prediabetes

MicroRNA-122-5p (miR-122) is primarily expressed in the liver and is increasingly released into the bloodstream during obesity. It impacts the function of non-liver tissues, such as vascular endothelial cells, and increases the risk of diabetic vasculopathy. Using a gamma-peptide-nucleic acid-based miR-122 inhibitor (γP-122-I), we show that miR-122 regulates blood glucose levels and endothelial function in high-fat diet-fed mice. Targeting γP-122-I to endothelial cells retains its ability to improve vascular function but reduces metabolic benefits compared to the non-targeted version. Our results show that endothelial cells take up miR-122 through a neuropilin-1-dependent mechanism. Aortic transcriptomic analysis implicates miR-122 role in mitochondrial function. The aortas of high-fat diet-fed mice receiving an inhibitor of miR-122 were more efficient in oxygen consumption despite a decline in the expression of mitochondrial electron transport chain complexes. Supporting these findings, the overexpression of miR-122 under hyperglycemic conditions decreases mitochondrial electron transport chain respiration and mitochondria with high membrane potential, indicating its detrimental impact on mitochondrial function. These findings support miR-122 as a therapeutic target for diabetic vasculopathy and support γPNA-based miR-122 inhibition as a potentially safer and more effective therapy.