Spatially Confined Intervention of Cellular Senescence by a Lysosomal Metabolism Targeting Molecular Prodrug for Broad‐Spectrum Senotherapy

Abstract Specific intervention of senescent cells (SnCs) is emerging as a powerful means to counteract aging and age‐related diseases. Canonical methods are generally designed to target SnC‐associated signaling pathways, which are however dynamically changing and highly heterogeneous in SnCs, significantly limiting the effectiveness. Here, we present a tailor‐made molecular prodrug targeting lysosome dysfunction, a unique feature shared by virtually all types of SnCs. The prodrug comprises three modules all targeting the altered lysosomal programs in SnCs, namely, a recognizing unit towards the elevated lysosome content, a linker cleavable by the activated lysosomal enzyme, and a lysosomotropic agent targeting the increased lysosomal membrane sensitivity. This spatially confined design enables killing broad‐spectrum SnCs, with high specificity over non‐SnCs. Along with in vivo benefits, this work offers a way to significantly expand the applicability of senotherapy in a wide range of diseases.