Mitochondria-Targeted Natural Antioxidant Nanosystem for Diabetic Vascular Calcification Therapy

The development of nanotherapy targeting mitochondria to alleviate oxidative stress is a critical therapeutic strategy for vascular calcification (VC) in diabetes. In this study, we engineered mitochondria-targeted nanodrugs (T4O@TPP/PEG–PLGA) utilizing terpinen-4-ol (T4O) as a natural antioxidant and mitochondrial protector, PEG–PLGA as the nanocarrier, and triphenylphosphine (TPP) as the mitochondrial targeting ligand. In vitro assessments demonstrated enhanced cellular uptake of T4O@TPP/PEG–PLGA, with effective mitochondrial targeting. This nanodrug successfully reduced oxidative stress induced by high glucose levels in vascular smooth muscle cells. In vivo studies showed prolonged retention of the nanomaterials in the thoracic aorta for up to 24 h. Importantly, experiments in diabetic VC models underscored the potent antioxidant properties of T4O@TPP/PEG–PLGA, as evidenced by its ability to mitigate VC and restore mitochondrial morphology. These results suggest that these nanodrugs could be a promising strategy for managing diabetic VC.