Mesoporous Ternary Nanozymes with Anti‐Senescence and Anti‐Inflammation Activities for Atherosclerosis Management

Abstract Numerous anti‐inflammatory agents and corresponding therapeutic strategies have been explored for treating inflammation‐related atherosclerosis, which has struggled with compromised antiatherosclerotic efficacy due to the complex pathogenesis. The senescent endothelial cells participate fundamentally at all stages in atherosclerosis, providing the basis for developing senotherapies to blunt the deleterious effects of senescent cells. In this work, a mesoporous palladium‐boron‐phosphorus ternary nanozyme with intrinsic superoxide dismutase/catalase‐mimicking properties is rationally engineered to co‐load H 2 (an anti‐inflammatory agent) within nanozyme's crystal lattice and 4,4′‐dimethoxychalcone (DIM, an anti‐senescence agent) within mesopores, which elicits strong anti‐inflammatory effect in pro‐inflammatory macrophages by elimination of reactive oxygen species (ROS), H 2 anti‐inflammation and promotion of cholesterol efflux, while simultaneously exerts anti‐senescence capacity in endothelial cells by protection of DNA from ROS damage and degradation of the cellular senescent components via autophagy activation. Both in vitro and in vivo experimental results verify the synergy between nanozyme‐based anti‐inflammatory therapy and autophagy activation, demonstrating that such a precise regulation of vascular senescence is applicable to augment antiatherosclerotic efficiency, which provides the nanomedicine‐enabled and senotherapy‐based paradigm for atherosclerosis management.