Photoactivated hydride therapy under hypoxia beyond ROS

As compared to oxidative phototherapy, studies on reactive reductive species-participating photodynamic therapy (PDT) are rare. Porphyrins are typical photosensitizers restricted by the oxygen level, but efficacy and selectivity are always incompatible in PDT. Herein, we report that phlorins are ideal hydride (H^-) donors and explore a water-soluble triphenylphosphonium-modified zinc-coordinated porphyrin (^mitoZnPor) for in situ photogeneration of zinc-cored phlorin (^mitoZnPhl). Driven by 1,4-dihydronicotinamide adenine dinucleotide (NADH), the ^mitoZnPor/^mitoZnPhl couple can reduce electron acceptors like iron heme and ubiquinone that play key roles in the mitochondrial electron transport chain (Mito-ETC). Under hypoxia, ^mitoZnPor showed excellent cancer-selectivity and a highly efficient in vitro PDT effect with IC₅₀ at nanomolar levels and potent tumor growth inhibition in a 4T1 tumor-xenografted mouse model with good biosafety, which underlines the great potential of Mito-ETC targeted non-classical PDT via a H^--transfer mechanism beyond reactive oxygen species (ROS) in precision cancer phototherapy using NADH as a biomarker and original electron donor.