Lesional Macrophage‐Targeted Nanomedicine Regulating Cholesterol Homeostasis for the Treatment of Atherosclerosis

Abstract The accumulation of atherosclerosis plaques within arterial walls leads to cardiovascular events. Lipid‐laden macrophages, known as foam cells play a pivotal role in atherosclerotic plaque progression by disrupting cholesterol homeostasis and facilitating inflammation. This study presents a rational and multivalent nanoplatform ( siT TENPs) for atherosclerosis treatment. siT TENPs can form electrostatic complexes with the nucleic acid siTRPM2 , thereby reducing oxidized low‐density lipoprotein (oxLDL) uptake by foam cells and alleviating inflammation. Concurrently, β‐cyclodextrin (β‐CD) modified siT TENPs facilitate cholesterol clearance, further re‐establishing lipid homeostasis. The nanometer size and S2P peptide (CRTLLTVRKC) modification endow these particles with specific targeting capabilities toward lesional macrophages, thereby enhancing their anti‐atherosclerotic efficacy. Consequently, the siT TENPs delivery system effectively inhibits pathological cholesterol internalization while simultaneously promoting cholesterol efflux mechanisms and reducing inflammation. This therapeutic intervention leads to significant regression of atherosclerotic plaque. This study introduces an innovative therapeutic strategy aimed at improving cholesterol homeostasis, with promising implications for the treatment of atherosclerosis.