In Situ Reprogramming of Senescent Microenvironment via Augmentation of Endogenous Senolytic Actions for Advanced Atherosclerosis Management

Advanced atherosclerosis (AS) poses substantial residual risk of life-threatening cardiovascular disease, even with optimized lipid-lowering therapies. Histopathological evaluation of clinically obtained specimens revealed that advanced plaques developed a distinct senescent microenvironment compared to early stage lesions, and senescent foam cells (FCs) are the culprits in creating the pathological microenvironment via initiating senescence-propagating crosstalk with multiple vascular cells. Herein, we synthesized a zeolitic imidazolate framework-8 (ZIF-8)-based nanomedicine denoted as L-pKNZ. Unlike conventional senolytic agents that primarily induce cellular apoptosis, L-pKNZ activates FC autophagy and enhances macrophage efferocytosis. This strategy established an endogenous senolytic system to relieve FC overload while simultaneously reprogramming the senescent microenvironment. Results from multiomics analysis aligned with outcomes from in vitro/in vivo experiments, all in favor of vascular rejuvenation and AS amelioration. Critically, we successfully radiolabeled L-pKNZs with the radionuclide ⁶⁸Ga, which allowed noninvasive in vivo imaging of the senescent microenvironment with micro-PET/CT. Overall, this study provides a versatile theranostic platform with broad implications for age-related diseases.