Leveraging on the efficient CRISPR-Cas–based gene deletion and capitalizing on the critical role of endothelial TXNDC5 in DF-induced atherosclerosis, we devised a new approach integrating nanocarriers and CDH5-driven CRISPR-Cas9 plasmids to specifically delete Txndc5 in vascular endothelium, resulting in increased eNOS protein and reduced atherosclerosis in ApoE−/− mice. Here, NOS3 is linked to atherosclerosis.