Angew Chem Int Ed Engl. 2026 Aug 28:e5856873. doi: 10.1002/anie.5856873. Online ahead of print.

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.

PMID:42665947 | DOI:10.1002/anie.5856873