Nanoparticle-based antioxidants suppress angioplasty-induced neointimal hyperplasia in rat carotid arteries

Oxidative stress and vascular inflammation predominantly influence restenosis following angioplasty, causing neointimal hyperplasia. Conventional antioxidants are rapidly eliminated and inadequately localized to injured vessels. We evaluated nitroxide radical-containing nanoparticles (RNPs), polymeric micelles covalently conjugated with 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl, in a rat carotid artery balloon injury model. Rhodamine-labeled RNPs selectively accumulated at the injured endothelium and penetrated into the neointima and media. RNPs significantly reduced intimal area, intima-to-media ratio, and preserved lumen patency compared with saline and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL). Mechanistic analyses revealed suppression of reactive oxygen species and oxidized low-density lipoprotein accumulation, LOX-1 expression attenuation, E-selectin-positive endothelial cell reduction, and decreased proinflammatory M1 macrophage infiltration. These findings demonstrate that RNPs effectively suppress angioplasty-induced neointimal hyperplasia through selective vascular accumulation and sustained radical scavenging. Therefore, antioxidant nanomedicine represents a promising therapeutic approach distinct from conventional antioxidants or drug-eluting stents, with translational potential for restenosis prevention.