All-in-one molecular design of activatable phototheranostic platform for potent hypoxia-tolerant photodynamic immunotherapy of cancer

Fluorescence imaging-guided photodynamic therapy (PDT) offers immense clinical potential for cancer treatment. However, their therapeutic efficacy and biosafety are compromised by the high oxygen dependency of traditional Type II photosensitizers and insufficient targeting accuracy. Herein, we present a tumor-organelle-targeted and activatable phototheranostic platform (termed NO₂/BDP-BT), which was engineered via an atom-economical all-in-one design strategy. The NO₂/BDP-BT gathers exceptional tumor-organelle targeting ability, nitroreductase (NTR)-activated fluorescence enhancement, allowing it to monitor hypoxia levels in biosystems (living cells, clinical patient tissues, and in vivo). Moreover, it enables the generation of Type I/II reactive oxygen species (ROS) in situ after NTR activation, thereby suppressing tumor growth with an inhibition rate of 93.2 % via mitochondria-mediated apoptosis and potentiating the antitumor immunity response. Cocrystal structural analysis of the NTR protein in complex with the precursor of NO₂/BDP-BT (PDB: 7XWW; resolution: 2.80 Å) first reveals that multiple non-covalent interactions (e.g., hydrogen bonding and π-π stacking) make it anchor in the catalytic environment with high affinity. Moreover, NO₂/BDP-BT can be expanded to a Type I PDT photosensitizer (NO₂/BDPS-BT) by introducing a thiophene unit, conquering hypoxia restriction in PDT. This work establishes a molecular platform of activatable phototheranostic sensor with potent therapeutic efficacy and biosafety, which would effectively address both hypoxia resistance and targeting deficiencies inherent in conventional PDT.