Aberrant lipid accumulation in both endothelial cells and macrophage foam cells as well as atherogenic inflammation in the atherosclerotic lesions, if left untreated, eventually lead to plaque rupture and arterial damage, causing devastating consequences. In this report, we explore a dual cell therapy modality by designing a dual-targeting core-shell nanoplatform to deliver siRNA against lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1 siRNA) and atorvastatin (AT) to control lipid trafficking to and from endothelial cells and macrophages in the atherosclerotic lesions selectively and sequentially. The core-shell nanoparticles are composed of a poly(D,L-lactide-co-glycolide) (PLGA) core for AT encapsulation and siRNA complexation and three external layers: a lipid bilayer as the inner layer for cholesterol receiving, apolipoprotein A-I (apoA-I) as the intermediate layer for macrophage targeting, and hyaluronic acid (HA)-DOPE as the outermost layer for endothelial cell targeting. The nanoplatform is designed such that it can shed the HA-DOPE layer extracellularly upon encountering HAase type II (Hyal-2) to expose the intermediate apoA-I layer for enhanced entry into macrophages. We thoroughly characterized dual-targeting bifunctional core-shell nanoparticles and studied the dual-targeting mechanism and biofunctions of the nanoplatform both in vitro and in vivo. Following a 12-week biweekly dosing regimen, the core-shell nanoparticles coated with high molecular weight HA (200 kDa) exhibited the most potent anti-atherosclerotic activities as evidenced by 39% plaque size reduction, 63% decrease in lipid accumulation, 68% reduction in CD68 + macrophage content and 74% reduction in monocyte chemoattractant protein 1 (MCP-1) content compared with the baseline group. Taken together, the dual-targeting bifunctional core-shell nanoparticles exert a synergistic therapeutic effect on both endothelial cells and macrophages as a dual cell therapy modality to regress atherosclerotic plaques.