Pathological Mechanism-Inspired Biomimetic Nano-Senotherapy for Reversing Experimental Atherosclerosis in ApoE-/- Mice

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 (K₂A) from the MPO-inhibitory tripeptide KYC, which co-assembles with the senolytics Navitoclax into a nano-Senotherapy (N@K₂A). Further cloaked with neutrophil membranes from AS mice, the biomimetic N@K₂A@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.