<p>Atherosclerosis (AS) is a chronic inflammatory disease characterized by vascular endothelial dysfunction. In the early stage of the disease, endothelial cell injury induces the infiltration of inflammatory macrophages, which secrete large amounts of inflammatory factors, further aggravating endothelial cell dysfunction and exacerbating the disease. Therefore, it is promising for co-targeting endothelial cells and macrophages further regulating the inflammatory microenvironment and endothelial cell function for effective treatment. The current nano-drug delivery system (NDDS) for AS treatment is mainly focused on anti-inflammatory therapy, while ignoring the potential value of suppressing inflammation and simultaneously improving vascular endothelial function. In this study, a pH-responsive dual-targeted NDDS based on plaque microenvironment, BC@CS/cRGD NPs, was prepared by combining baicalin (BC) with chondroitin sulfate (CS) through amidation reaction, and further modified with a targeting group cRGD peptide. In vitro release experiments illustrated a faster release of the nanoparticle at pH 5.0 than at pH 7.4. Meanwhile, in vitro cellular experiments demonstrated its ability to target activated endothelial cells and macrophages. In a mouse model of AS, BC@CS/cRGD NPs accumulated at plaque sites and effectively attenuated the plaque progression. In conclusion, this pH-sensitive BC@CS/cRGD NPs offered a very potential strategy for modulating endothelial dysfunction and inflammatory microenvironment for the treatment of AS.</p> Graphical Abstract <p></p>