<p>Macrophage-like phenotype switching of vascular smooth muscle cells (VSMCs) is a crucial mechanism driving atherogenesis. Inhibition of a phenotype switch to macrophage-like cells is a promising strategy to prevent atherosclerosis (AS), and targeted nanotherapeutics represent one approach for implementing this strategy. To this end, we designed immunosuppressive oligodeoxynucleotide A151 functionalized selenium nanoparticles with a spearhead LacNAc (LN-A151-SeNPs) that target macrophage-like VSMCs. Nano characterization showed that the uniformity and stability of nanoparticles were optimized by modification with LacNAc and A151, resulting in an average diameter of 88.90 ± 1.45&#xa0;nm, Zeta potentials of -21.1 ± 1.5 mV, a A151:Se molar ratio of 1:60 and mass ratio of 1.68:1. The effects of LN-A151-SeNPs on inhibiting VSMCs phenotype switching and attenuation of AS were investigated using <i>ApoE</i>^{<i>−/−</i>} mice fed a high-fat/high-cholesterol diet, combined with a cellular model in which VSMCs treated with cholesterol. Results showed that LN-A151-SeNPs accumulated in aorta and targeted macrophage-like VSMCs in atherosclerotic plaques as assessed by fluorescence tracing and detection of co-localization with Galectin-3. LN-A151-SeNPs inhibited the phenotypic changes of VSMCs into macrophage-like cells by upregulating α-SMA and downregulating CD68 expression, leading to the reduction of plaque formation. Mechanistically, LN-A151-SeNPs inhibited activation of the NLRP3 inflammasome, with decreased differentiation of VSMCs into a pro-AS phenotype. Moreover, LN-A151-SeNPs mitigated oxidative stress in VSMCs by triggering selenoprotein synthesis and bioactivity, particularly selenium-dependent enzymes. Thus, these results suggest that LN-A151-SeNPs restrain atherogenesis by targeting VSMCs to suppress phenotype switching and oxidative stress, indicating the translational potential of A151 functionalized selenium nanoparticles for AS therapy.</p> Graphical abstract <p></p>