{"id":"doi:10.1002/advs.78139","kind":"article","title":"Orthogonal Light- and Enzyme-Triggered and-Gate Prodrugs for Senolytic Therapy","authors":["Chang M","Zhang K","Wang J","Bi F","Dai Z","Yang M","Liu M","Peng H","Zhang F","Guo Y","Dai J","Liu Q","Wang W"],"author_count":13,"year":2026,"published":"2026-10-04","venue":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","cited_by":0,"doi":"10.1002/advs.78139","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1002/advs.78139","archive_url":"https://space-kitty.com/papers/doi:10.1002/advs.78139","updated":null,"pmid":"42829921","pmcid":"PMC13634484","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC13634484/pdf","abstract":"Senescence-associated β-galactosidase (SA-β-gal) is widely used to target senescent cells, but its activity in non-senescent tissues can limit selectivity. Here, we developed a light-enzyme AND-gate strategy in which an o-nitrobenzyl photocage blocks β-galactoside cleavage until 390 nm irradiation. The strategy was evaluated using a fluorescent probe (LS-C), a doxorubicin prodrug (LS-D), and an ARV-771-based PROTAC (LS-A). LS-C exhibited dual-trigger-dependent fluorescence activation, while LS-D preferentially induced apoptosis and LS-A promoted BRD4 degradation in senescent cells following light activation. Across multiple senescence models, LS-D and LS-A showed higher senolytic indices than their corresponding parent compounds. In senescent lung cancer patient-derived organoids, LS-D combined with light increased organoid death, whereas either treatment alone had minimal effects. These results provide proof-of-concept evidence for sequential light-enzyme AND-gating as a strategy for controlling payload activation in senescent cells under the tested in vitro and ex vivo conditions.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Orthogonal Light- and Enzyme-Triggered and-Gate Prodrugs for Senolytic Therapy\" by Chang M, Zhang K, Wang J et al., https://doi.org/10.1002/advs.78139, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"aging-longevity","name":"Biology of Aging & Longevity","domain_slug":"medicine"}],"cited_in_dossiers":[]}