Atherosclerosis, a complex vascular disease, is increasingly recognized as an immunometabolic disorder due to the intricate interplay between inflammatory cytokines, blood-borne leukocytes, hyperlipidemia, and vascular cells during lesion development. During my doctoral studies, I focused on investigating cholesterol metabolism and inflammation within atherosclerotic macrophages, aiming to develop novel therapeutic methods. In chapter two, my research aimed to uncover a non-canonical signaling pathway triggered by interferon gamma, which plays a role in excessive cholesterol uptake by macrophages in individuals with obesity and insulin resistance. This excessive cholesterol uptake leads to larger atherosclerotic lesions and contributes to the increased risk of cardiovascular disease observed in patients with obesity and insulin resistance. To explore this pro-atherogenic pathway, I utilized in vivo models of atherosclerosis, conducted phosphoproteomic analyses, and employed small molecule inhibitors. In Chapter Three, my study focused on leveraging the activation of liver X receptor (LXR) in macrophages to promote cholesterol efflux, thereby reducing the size of atherosclerotic lesions. To accomplish this, I used a DNA nanodevice that conjugated to an LXR agonist, enabling targeted modulation of LXR activation to macrophages without the typical side effect of hypertriglyceridemia in the liver. Through this innovative approach, I demonstrated the potential of new therapeutic strategies in addressing atherosclerosis. Additionally, I investigated the mechanism of metabolism and drug release of the DNA nanodevice, confirmed its targeting of LXR, and demonstrated its efficacy in vivo. Overall, this research enhances our understanding of the intricate connections between cholesterol metabolism, inflammation, and atherosclerosis, while also highlighting promising strategies for targeted intervention in this prevalent cardiovascular disease.