ICAM-1 targeted extracellular vesicles loaded with HC-070 mitigate vascular oxidative stress and inflammation in obstructive sleep apnea hypopnea syndrome by inhibiting TRPC5

Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS) significantly contributes to cardiovascular diseases through severe endothelial dysfunction, a pathology driven primarily by chronic intermittent hypoxia (CIH)-induced oxidative stress and inflammation. Current interventions inadequately address this vascular component. Human umbilical mesenchymal stem cell-derived extracellular vesicles (HUMSC-EVs) have regenerative potential, but improved targeting is needed to maximize therapeutic efficacy. This study sought to engineer and evaluate Intercellular Adhesion Molecule 1 (ICAM-1) targeted EVs loaded with the Transient Receptor Potential Channel C5 (TRPC5) inhibitor HC-070 (ICAM-1⁺H-EVs) for their ability to ameliorate oxidative damage in OSAHS. We employed a CIH mouse model and IH-treated HUVECs, and characterized ICAM-1⁺H-EVs using Western blotting and ExoView. ICAM-1⁺H-EVs significantly enhanced HUVEC uptake and, in both in vivo and in vitro settings, alleviated oxidative stress by lowering Reactive Oxygen Species (ROS) and Malondialdehyde (MDA) levels and restoring the activities of antioxidant Enzymes Superoxide Dismutase (SOD) and Glutathione Peroxidase (GSH-PX). Furthermore, ICAM-1⁺H-EVs substantially suppressed inflammation by lowering TNF-α and IL-6 levels and mitigated mitochondrial ROS and morphological damage. This novel strategy targets TRPC5-mediated calcium influx, providing a potent therapeutic approach to interrupt the oxidative stress and inflammatory cycle driving OSAHS-associated vascular dysfunction.