Atherosclerosis is the main pathogenic factor of various cardiovascular diseases. During the pathogenesis of atherosclerosis, macrophages play a major role, mainly by secreting pro-inflammatory cytokines and taking in lipids to form foam cells. Thiamine pyrophosphate (TPP) is an antagonist of the P2Y6 receptor, which is overexpressed on macrophages during atherosclerosis and facilitates the lipid phagocytosis of macrophages. However, the excessive accumulation of TPP may interfere with some vital metabolic processes like the tricarboxylic acid cycle, oxidative phosphorylation and the pentose phosphate pathway. Herein, we designed and constructed a nanoparticle ZIF-8@TPP for the treatment of atherosclerosis. The as-established ZIF-8@TPP nanoplatform exhibited specific cytotoxicity towards macrophages in vitro. Meanwhile, histological analysis confirmed the excellent therapeutic efficacy of ZIF-8@TPP in vivo. Mechanistic studies indicated that ZIF-8@TPP potentially lowered lipid phagocytosis and lipid metabolism of macrophages via the PI3K/AKT/MSR1 pathway. This study also demonstrated that the anti-atherosclerotic effect of TPP was enhanced after combination with a prototypical metal-organic framework (MOF), ZIF-8. This synergistic controlled-release drug delivery system may provide a novel idea for anti-atherosclerosis therapy by combining reagents that can inhibit lipid phagocytosis of macrophages with MOFs.