Engineering Hierarchical Recognition-Mediated Senolytics for Reliable Regulation of Cellular Senescence and Anti-Atherosclerosis Therapy

Precise regulation of vascular senescence represents a far-reaching strategy to combat age-related diseases. However, the high heterogeneity of senescence, alongside the lack of targeting and potent senolytics, makes it very challenging. Here we report a molecular design to tackle this challenge through multidimensional, hierarchical recognition of three hallmarks commonly shared among senescence, namely, aptamer-mediated recognition of a membrane marker for active cell targeting, a self-immolative linker responsive to lysosomal enzymes for switchable drug release, and a compound against antiapoptotic signaling for clearance. Such senolytic can target and trigger severe cell apoptosis in broad-spectrum senescent endothelial cells, and importantly, distinguish them from the quiescent state. Its potential for in vivo treatment of vascular diseases is successfully illustrated in a model of atherosclerosis, with effective suppression of the plaque progression yet negligible side effects.