Atherosclerosis is an inflammatory disease characterized by lipid deposition, inflammatory cell infiltration, and plaque formation, representing a primary underlying cause of cardiovascular diseases. The complex pathogenesis of atherosclerosis limits the effectiveness of current therapies, which often demonstrate suboptimal efficacy. In this study, we developed a nanocarrier-based delivery system combining fragile histidine triad protein (FHIT) with the copper-tetrakis(4-carboxyphenyl)porphyrin metal-organic framework (Cu-TCPP MOF) for atherosclerosis treatment. Due to the central role of macrophages in atherosclerosis progression, this system was designed to exert its effects primarily on macrophages. Mechanistic investigations revealed that the combined application of FHIT and the Cu-TCPP MOF enhances reactive oxygen species (ROS) production, leading to inhibition of the PI3K/AKT signaling pathway and subsequent induction of macrophage apoptosis. In vivo studies demonstrated that this combined treatment approach effectively reduces atherosclerotic lesions, supporting its therapeutic potential. Our findings suggest that this nanocarrier-based combination strategy may offer an improved therapeutic approach for atherosclerosis management.