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Here, we developed a light\u2013enzyme AND\u2010gate strategy in which an o\u2010nitrobenzyl photocage blocks \u03b2\u2010galactoside cleavage until 390\u00a0nm irradiation. The strategy was evaluated using a fluorescent probe (LS\u2010C), a doxorubicin prodrug (LS\u2010D), and an ARV\u2010771\u2010based PROTAC (LS\u2010A). LS\u2010C exhibited dual\u2010trigger\u2010dependent fluorescence activation, while LS\u2010D preferentially induced apoptosis and LS\u2010A promoted BRD4 degradation in senescent cells following light activation. Across multiple senescence models, LS\u2010D and LS\u2010A showed higher senolytic indices than their corresponding parent compounds. In senescent lung cancer patient\u2010derived organoids, LS\u2010D combined with light increased organoid death, whereas either treatment alone had minimal effects. These results provide proof\u2010of\u2010concept evidence for sequential light\u2013enzyme AND\u2010gating as a strategy for controlling payload activation in senescent cells under the tested in vitro and ex vivo conditions.<\/jats:p>","DOI":"10.1002\/advs.78139","type":"journal-article","created":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T16:00:12Z","timestamp":1791129612000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Orthogonal Light\u2010 and Enzyme\u2010Triggered and\u2010Gate Prodrugs for Senolytic Therapy"],"prefix":"10.1002","author":[{"given":"Mengyang","family":"Chang","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Biology Eastern Institute of Technology  Ningbo Zhejiang People's Republic of China"},{"name":"Department of Thoracic Surgery Xinqiao Hospital Army (Third Military) Medical University  Chongqing People's Republic of 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