摘要
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 choles-terol 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 in vitro and in vivo.This“two-birds-one-stone”nanotherapeutic offers a novel approach for regulating vascular microenvironment ho-meostasis and improving therapeutic efficiency in atherosclerosis treatment.
基金
support from the National Key Research and Development Projects(Grants No.2023YFC2306500)
Shanghai Shuguang Program(Grant No.21SG39)
Shanghai Natural Science Foundation(Grant No.23ZR1447800)
Xuhui District’s Key Medical Disciplines(Grant No.SHXHZDXK202319).
