Targeted Lipid Transfer Nanoshuttle via Lipid‐Specific Transcytosis Induces Atherosclerotic Plaque Regression

Abstract Lipid transfer proteins (LTPs) orchestrate inter‐membrane lipid transport through hydrophobic cavities, but their therapeutic application is limited by the requirement to simultaneously maintain dual‐membrane targeting and lipid‐carrying structures. Inspired by LTPs, a therapeutic platform coupling β‐cyclodextrin (β‐CD) with gold nanoparticles as a lipid‐capturing shuttle (LipShuttle) is proposed. The β‐CD specifically targets lipid droplets to sequester stored lipids, while the gold nanoparticles drive transcytotic lipid efflux. This dual mechanism enhances lipid removal, boosts neutral lipid catabolism, and reverses lipid overload in foam cells. Then LipShuttle's therapeutic efficacy is validated in high‐fat diet‐fed ApoE − / − mice with established atherosclerotic plaques. By combining ultrasound‐enhanced lipid efflux with cell targeting, LipShuttle promotes plaque regression and reduces vulnerability. Mechanistically, LipShuttle‐mediated lipid depletion suppresses arachidonic acid metabolism, attenuating inflammation, and reprograms plaque macrophages toward a pro‐efferocytic phenotype. This dual action promotes plaque regression, demonstrating a promising lipid transfer‐based therapeutic strategy for diseases driven by dysregulated lipid accumulation.