摘要
The rupture of atherosclerosis(AS)vulnerable plaque is the major cause of fatal arterial thrombosis related diseases.The lipid dysbolism and pro-inflammatory microenvironment are considered two main driving factors for plaque rupture.Herein,a“two-pronged”nanosystem LCS-Se/Res was designed to efficiently stabilize AS plaques,by precisely regulating lipid metabolism and inflammatory microenvironment.LCS-Se/Res was constructed with the core of resveratrol(Res)loaded selenium(Se)nanoparticles(NPs),and the shell(LCS)of targeting peptide(LSIPPKA)modified chitosan(CS).This system was stable in blood circulation.When it arrived at the plaque site,LCS-Se/Res could actively recognize the highly expressed lectin-like oxidized low-density lipoprotein receptor 1(LOX-1)receptor and accumulate there.Thereafter,Res was released from LCS-Se nanocarriers in situ by responding to acidic plaque microenvironment.On the one hand,Res increased autophagy flux in damaged endothelial cells by activating cAMP-PKA-AMPK-SIRT1 signaling pathway to promote lipid degradation.Interestingly,LCS-Se also promoted cholesterol efflux to improve lipid metabolism.On the other hand,fixed-point separated Res and LCS-Se synergistically improved plaque inflammatory microenvironment by reversing macrophage phenotype(M1 to M2)and alleviating plaque oxidative stress.Pharmacodynamics result proved that the plaque vulnerability index(VI)decreased from 1.39±0.282 to 0.108±0.02 after LCS-Se/Res treatment.In short,this study provided a new therapeutic strategy for the atherosclerosis through the two-pronged approach.
基金
supported by the National Natural Science Foundation of China(No.82102918).
