Donor-PeT Control of Intersystem Crossing Enables ALDH1A1-Activated Photodynamic Therapy

Aldehyde dehydrogenase 1A1 (ALDH1A1) is highly expressed in therapy-resistant and metastatic cancers and represents a clinically relevant biomarker for selective activation strategies. We report AAP, an OFF-ON photosensitizer activated through ALDH1A1-mediated oxidation that produces singlet oxygen upon light exposure. AAP uses a donor photoinduced electron transfer (d-PeT) mechanism to suppress intersystem crossing in its unreacted benzaldehyde form, which minimizes background activity. Oxidation by ALDH1A1 disrupts d-PeT and restores phototoxicity. AAP showed minimal off-target activation by other ALDH isoforms or oxidative stress. In vivo, AAP suppressed tumor growth in two non-small cell lung cancer (NSCLC) models. In the first, intratumoral delivery into established tumors confirmed efficacy and ALDH1A1 dependence. In the second, liposomal AAP enabled intravenous delivery to early stage lesions with limited vascularization where treatment remained effective. These findings establish d-PeT suppression of intersystem crossing as an effective chemical biology strategy for enzyme-activated photodynamic therapy.