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 lipoph...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.展开更多
基金support from the National Key Research and Development Projects(Grants No.2023YFC2306500)Shanghai Shuguang Program(Grant No.21SG39)+1 种基金Shanghai Natural Science Foundation(Grant No.23ZR1447800)Xuhui District’s Key Medical Disciplines(Grant No.SHXHZDXK202319).
文摘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.
