Redox-Responsive Mitochondrial Delivery from Functionalized Vascular Stent Surfaces

Abstract

Mitochondrial dysfunction and oxidative stress are key contributors to impaired vascular healing following stent implantation. Although drug-eluting stents reduce restenosis, they do not promote tissue regeneration or correct cellular metabolic deficits. A redox-responsive mitochondrial delivery system is developed for localized therapeutic release from vascular stent surfaces. Intact mitochondria are immobilized onto Nitinol substrates through a stepwise surface modification strategy incorporating a reactive oxygen species (ROS)-cleavable linker. Upon exposure to elevated ROS levels, mitochondria are released in a dose-dependent manner and internalized by human endothelial cells and vascular smooth muscle cells. Transmission electron microscopy confirms the integrity of isolated mitochondria, and X-ray photoelectron spectroscopy and secondary ion mass spectrometry validate successful surface functionalization and grafting. The modified surfaces demonstrate high biocompatibility, with minimal cytotoxicity and reduced platelet adhesion. Released mitochondria restore mitochondrial membrane potential, oxygen consumption rate and enhance cell viability under oxidative stress. Ex vivo assessment in rat aortic tissue provides visual confirmation of mitochondrial uptake in a physiologically relevant context. This platform establishes a stimulus-responsive, organelle-based therapeutic strategy that targets mitochondrial dysfunction at the biomaterial–tissue interface and offers potential to enhance vascular regeneration in oxidative microenvironments following endovascular interventions.