A Zombie Macrophage‐Based “Trojan horse” Enhances the Effect of Efferocytosis Through Immune Regulation for Atherosclerosis Treatment

Abstract Various immune cell‐mediated drug delivery systems have been reported for precision medicine, but the proinflammatory differentiation of immunocyte vehicles can exacerbate disease progression, resulting in a formidable obstacle to efficacious pharmacotherapy. The progression of atherosclerosis is closely related to the recruitment of blood immunocytes into the plaques, as the migrated macrophages can differentiate into harmful foam cells, leading to dysregulation of macrophage immunity. In this study, a “Trojan horse” based on zombie macrophages (denoted as Z‐Møs) as a biomimetic drug delivery system (denoted as ZARMs) is constructed to regulate macrophage immunity inside plaques. Reactive oxygen species‐responsive nanoparticles (denoted as AR‐NPs) loaded with atorvastatin (denoted as ATT) are encapsulated into Z‐Møs to construct ZARMs. After intravenous administration, ZARMs selectively migrate into plaques, and insusceptible biological characteristics are kept even in the presence of high levels of ROS within the plaques, which simultaneously triggers ATT release from AR‐NPs loaded in Z‐Møs. Treatment assessments indicate that ZARMs can efficiently boost macrophage immunity to reduce the inflammatory burden by inhibiting the expression of CD47 on foam cells without the risk of detrimental domestication of immunocytes in the plaques. This Z‐Møs‐mediated drug delivery system may arouse an advanced therapeutic strategy for preventing atherosclerotic cardiovascular disease.