Macrophage-targeting Antisenescence nanomedicine enables in-Situ NO induction for Gaseous and antioxidative atherosclerosis intervention

Senescent-endothelial cells significantly accelerate atherosclerosis progression, making the mitigation of cellular aging a promising strategy for treating the disease. Nitric oxide (NO), a low molecular weight and lipophilic gas, has been shown to penetrate cell membranes effectively and delay cell senescence. In this study, we designed and engineered osteopontin (OPN)-modified nanoliposomes (CZALO) that encapsulate L-arginine (L-Arg) and cerium-zirconium oxide nanoparticles (CZ NPs), which exhibit enzyme-like activities for targeted atherosclerosis treatment. Following inflammatory chemotaxis and OPN-mediated internalization by macrophages, CZ NPs released from CZALO nanoliposomes significantly scavenge reactive oxygen species, thereby inhibiting cholesterol uptake and promoting macrophage phenotypic transformation, resulting in both antioxidant and anti-inflammatory effects. Additionally, nitric oxide synthase (NOS) overexpressed in macrophages catalyzes L-Arg to produce NO, which is then selectively released in situ and diffuses into endothelial cells, exerting anti-aging effects by regulating senescence-associated secretory phenotype factor secretion, enhancing lysosomal function, alleviating cell cycle arrest, and reducing DNA damage. The antioxidant and anti-aging effects of CZALO nanoliposomes collectively alleviate atherosclerotic burden with minimal toxicity both <i>in vitro</i> and <i>in vivo</i>. This "two-birds-one-stone" nanotherapeutic offers a novel approach for regulating vascular microenvironment homeostasis and improving therapeutic efficiency in atherosclerosis treatment.