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.