# Orthogonal Light- and Enzyme-Triggered and-Gate Prodrugs for Senolytic Therapy

Article · 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

- Archive id: doi:10.1002/advs.78139
- Published: 2026-10-04
- Venue: Advanced science (Weinheim, Baden-Wurttemberg, Germany)
- DOI: https://doi.org/10.1002/advs.78139
- PMID: 42829921
- PMCID: PMC13634484
- Citations: 0
- Source URL: https://doi.org/10.1002/advs.78139
- PDF: https://europepmc.org/articles/PMC13634484/pdf
- Provenance: europepmc

## 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 reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Biology of Aging & Longevity](https://space-kitty.com/topics/aging-longevity)

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