Atherosclerosis (AS) is the most important pathological basis for cardiovascular diseases worldwide. However, the current mainstream therapeutic strategies for AS only target isolated pathological links, ignoring hepatic steatosis as a related risk factor for AS, which leads to limited effectiveness in controlling the overall course of atherosclerosis. Herein, a smart nanoplatform that can synergistically regulate AS and hepatic steatosis was first reported, which featured sulfide iron nanosheets as the core, grafted with bovine myeloid antimicrobial peptide 27 (BMAP-27), skillfully coated with an erythrocyte-macrophage hybrid biomimetic membrane. First, this nanoplatform is capable of targeting atherosclerotic plaques. When combined with low-intensity focused ultrasound, the nanoplatform markedly enhanced local drug accumulation. The localized temperature rise generated by near-infrared laser irradiation acted to open TRPV1 channels, facilitating Ca2+ entry. This increase in cytosolic Ca2+ activated autophagy in foam cells, upregulated ABCA1-mediated cholesterol efflux, and reduced oxidized low-density lipoprotein accumulation. Meanwhile, FPRM efficiently scavenged reactive oxygen species (ROS) within atherosclerotic plaques and synergized with BMAP-27 to suppress AS-related inflammation. Intriguingly, the classic hepatic accumulation-metabolism pathway of FPRM enabled continuous ROS elimination in the liver, effectively alleviating hepatic steatosis and lowering plasma triglyceride levels, thereby achieving metabolic reprogramming and ultimately inhibiting the progression of atherosclerosis.
