Letters in Drug Design & Discovery · Jun 2026
Copper indium selenium nanozyme for atherosclerosis therapy by redox rebalancing and senescence suppression
By Tian C, Wang R, Li Y et al.
Background Atherosclerosis is a leading cause of cardiovascular morbidity and mortality. It is initiated by endothelial injury and progresses through persistent oxidative stress, endothelial senescence, and macrophage foam cell formation. Although current therapies primarily target lipid metabolism and inflammation, effective strategies that catalytically eliminate reactive oxygen species (ROS) and alleviate vascular senescence remain limited. Objective This study aimed to develop biocompatible copper indium selenium nanozymes (CIS NPs) with antioxidant enzyme-mimicking activities and evaluate their therapeutic potential against oxidative stress, cellular senescence, and atherosclerosis progression. Methods CIS NPs were synthesized and comprehensively characterized for morphology, crystallinity, elemental composition, and colloidal stability. Their superoxide dismutase (SOD)- and glutathione peroxidase (GPx)-like catalytic activities were evaluated in cell-free systems. The antioxidant and anti-senescent effects of CIS NPs were investigated in hydrogen peroxide-induced human umbilical vein endothelial cells (HUVECs). Their effects on foam cell formation were assessed in RAW 264.7 macrophages using Dil-oxLDL uptake and Oil Red O staining. Therapeutic efficacy and biosafety were further evaluated in high-fat diet-fed ApoE -/- mice. Results CIS NPs exhibited dual SOD- and GPx-like catalytic activities, enabling sequential scavenging of superoxide anion (O 2 • − ) and hydrogen peroxide (H 2 O 2) . In HUVECs, CIS NPs significantly reduced intracellular ROS levels, attenuated oxidative injury, and alleviated cellular senescence, as evidenced by decreased SA-β-gal staining. In RAW 264.7 macrophages, CIS NPs reduced Dil-oxLDL uptake and lipid accumulation, thereby suppressing foam cell formation. In ApoE -/- mice, repeated intravenous administration of CIS NPs markedly decreased atherosclerotic plaque burden, vascular ROS accumulation, and senescent cell abundance, without obvious abnormalities in the preliminary histological, biochemical, and hemolysis assessments. Conclusions CIS NPs function as efficient antioxidant nanozymes that mitigate oxidative stress, endothelial senescence, and macrophage foam cell formation. By targeting multiple pathological processes involved in atherosclerosis, CIS NPs effectively attenuate disease progression in vivo and represent a promising nanotherapeutic strategy for the prevention and treatment of atherosclerosis.