A Multifunctional Redox-Responsive Catecholamine-Based Nanoplatform for Atherosclerosis Therapy

Cardiovascular disease remains the leading threat to human health, with both the number of cases and the incidence rate increasing annually. Atherosclerosis (AS) is the underlying cause of its pathogenesis. Targeting the hallmark features of atherosclerotic lesions, elevated inflammation, redox imbalance, and impaired endothelial barrier function,a plant polyphenol-based drug delivery system with dual redox-responsive capabilities was developed. The redox-responsive carrier was constructed using epigallocatechin-3-gallate (EGCG) and cystamine (Cys) and subsequently loaded with rapamycin(Rapa). The resulting nanoparticles (EGCG/Cys/Rapa) were systematically evaluated for their physicochemical properties, drug-release behavior, cytocompatibility, anti-inflammatory activity, biosafety, and targeting ability for injured blood vessels. The nanoparticles were spherical, 100–250 nm in size, smooth-surfaced, and had a drug loading efficiency of 7.4%. In vitro release studies demonstrated that in pathological microenvironments simulated by high levels of glutathione or hydrogen peroxide, the nanoparticles exhibited significantly enhanced Rapa release, indicating excellent dual redox-responsive release characteristics. Cellular evaluation confirmed that the nanoparticles were non-cytotoxic, selectively inhibited proliferation of human umbilical artery smooth muscle cells (HUASMCs), and effectively suppressed macrophage secretion of Interleukin-6 and Tumor Necrosis Factor-alpha, thereby exerting anti-inflammatory effects. Biosafety assessment revealed a hemolysis rate below 5% and no pathological damage to major organs. Moreover, the nanoparticles efficiently targeted injured blood vessels, enabling targeted drug delivery and therapy for AS lesions. Collectively, the EGCG/Cys/Rapa nanoparticles integrate redox-responsive, intelligent drug release, selective inhibition of HUASMCs, anti-inflammatory activity, favorable biosafety, and AS-lesion targeting, offering a promising nanoplatform for the precision treatment of atherosclerosis.