Senolytic Drugs Activated Only by Both Light and Enzymes for Targeted Therapy

LS-D combined with light increased organoid death in senescent lung cancer patient-derived organoids.

• Senescence-associated β-galactosidase activity may limit selectivity when targeting senescent cells.
• A light-enzyme AND-gate strategy was developed to control the activation of compounds in senescent cells.
• The fluorescent probe LS-C showed dual-trigger-dependent fluorescence activation.
• The doxorubicin prodrug LS-D preferentially induced apoptosis in senescent cells upon light activation.
• The ARV-771-based PROTAC LS-A promoted BRD4 degradation in senescent cells following light exposure.
• LS-D and LS-A demonstrated higher senolytic indices in various senescence models compared to their parent compounds.

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