Pathological Mechanism‐Inspired Biomimetic Nano‐Senotherapy for Reversing Experimental Atherosclerosis in ApoE ^−/− Mice

ABSTRACT The greatest challenge in atherosclerosis (AS) management lies in achieving lesion reversal, not merely slowing progression. Senescent cell accumulation—driven by continuous generation and apoptotic resistance—perpetuates plaque pathology and obstructs regression. This study addresses the reversal conundrum through a dual‐action strategy: blocking new senescent cell formation while enhancing clearance of existing senescent cells. We developed a ROS‐responsive dimeric prodrug (K ₂ A) from the MPO‐inhibitory tripeptide KYC, which co‐assembles with the senolytics Navitoclax into a nano‐Senotherapy (N@K ₂ A). Further cloaked with neutrophil membranes from AS mice, the biomimetic N@K ₂ A@NEM precisely targets plaques, responds to local ROS, and orchestrates senescent cell formation and removal. This targeted senotherapeutic intervention demonstrates effective reversal of established experimental AS, offering a potential solution to the field's most pressing clinical dilemma.