Dual Activated Senolytic Prodrug

We present the concept of a precise senolytic prodrug activated in a two-stepmanner, functioning as a chemical AND gate. This design ensures therelease of a cytotoxic agent exclusively in senescent cells thatsimultaneously exhibit two key hallmarks of senescence: increased β-D-galactosidase activity detectable at suboptimal pH ≈6 (the commonly usedsenescence marker SA-β-gal) and elevated levels of reactive oxygen species(ROS), particularly hydrogen peroxide. Strategic Update (Version 2):Subsequent biological analysis identified a potential subcellular compartment mismatch between the enzymatic (lysosomal SA-β-galactosidase) trigger and the proposed ROS/boronate trigger, which may limit the reliability of a dual-gate mechanism in vivo. Given the translational constraints of topical delivery and the validated performance of single-gate galactoside prodrugs, the development strategy has been revised to prioritize a simpler SA-β-gal-activated architecture.