Bioorthogonal\nActivation of Deep Red Photoredox Catalysis\nInducing Pyroptosis

The\nrevolutionary impact of photoredox catalytic processes has\nignited novel avenues for exploration, empowering us to delve into\nnature in unprecedented ways and to pioneer innovative biotechnologies\nfor therapy and diagnosis. However, integrating artificial photoredox\ncatalysis into living systems presents significant challenges, primarily\ndue to concerns over low targetability, low compatibility with complex\nbiological environments, and the safety risks associated with photocatalyst\ntoxicity. To address these challenges, herein, we present a novel\nbioorthogonally activatable photoredox catalysis approach. In this\napproach, potent photocatalyst selection via atom replacement of the\nrhodamine core yielded the bioorthogonally activatable photocatalyst\n(<b>PC-Tz</b>). The introduction of 1,2,4,5-tetrazine quenched\nits photocatalytic properties, which were restored upon an intracellular\ninverse electron-demand Diels–Alder (iEDDA) reaction with <i>trans</i>-cyclooctene (TCO) localized in mitochondria. This\nreaction led to remarkable photocatalytic oxidation of nicotinamide\nadenine dinucleotide (NADH), effectively manipulating the mitochondrial\nelectron transport chain (ETC) under hypoxic conditions in cancer\ncells. Additionally, photocatalytic pyroptotic cell death was observed\nthrough a caspase-3/gasdermin E (GSDME) pathway, achieving notable\nantitumor efficacy and adenosine triphosphate (ATP) reduction in tumor\ncells. To the best of our knowledge, this represents the first example\nof bioorthogonally activatable photoredox catalysis, opening new avenues\nfor chemists to spatiotemporally control activity in specific cell\norganelles without disrupting other native biological processes.