ALDH Inhibition‐Primed Photocatalysis Disrupts Cancer Stemness Plasticity

Vollständiger Abstract

Worum geht es in dieser Arbeit?

ABSTRACT Light‐driven photoredox catalysis can shift intracellular NADH/NAD + balance by oxidizing NADH, but intracellular NADH pools are dynamically replenished through enzyme‐coupled redox metabolism. We show that ALDH‐mediated restoration of NADH/NAD + balance can buffer photoredox‐induced NADH depletion, providing a design rationale for coupling enzyme inhibition with photoredox catalysis. To counteract this redox‐buffering process, we introduce an enzymatic–photocatalytic strategy, termed E–PC, that integrates ALDH inhibition with NIR‐driven photocatalytic NADH oxidation within a single molecular construct. A small‐molecule conjugate, DE‐Et , was constructed by covalently linking DEAB, which can inhibit ALDH, to a near‐infrared (NIR)–active Nile Blue Sulfide–derived photocatalyst (NBS) through a ROS‐cleavable thioacetal linker. Upon NIR irradiation, DE‐Et releases DEAB while catalytically oxidizing intracellular NADH through single‐electron transfer, thereby attenuating ALDH‐mediated redox restoration and sustaining NADH/NAD + imbalance. This dual action compromises mitochondrial ATP production and activates caspase‐3/GSDME‐dependent pyroptosis. In stemness‐enriched tumor models, DE‐Et suppresses ALDH activity, clonogenic growth, spheroid integrity, and tumor growth in vivo. Local photoactivation further promotes systemic antitumor immune responses, consistent with immunogenic pyroptotic cell death. E–PC thus establishes a chemical strategy for light‐activated co‐delivery of photoredox catalysis and inhibition of a tumor‐overexpressed enzyme, converting an adaptive enzymatic buffer into a therapeutic vulnerability.