Fluorinated Hypoxia‐Responsive Aza‐BODIPY for NIR‐II FL/ ¹⁹ F MR/PA Imaging and Phototherapy of Lung Cancer

ABSTRACT Tumor hypoxia limits the efficacy of photodynamic therapy (PDT), necessitating photosensitizers with hypoxia‐adaptive therapy and imaging. Here, we present a fluorinated N ‐oxide aza‐BODIPY ( OFBD ) nanoemulsion ( OFBD‐NP ) for hypoxia‐responsive, multimodal imaging‐guided phototherapy. OFBD generates robust singlet oxygen under normoxia for PDT, but is reduced by CYP450 enzymes in hypoxic cells to photothermal‐potent FBD , enabling switchable PDT/PTT. Co‐assembly with fluorinated oil enhances oxygen delivery, boosts ¹⁹ F MRI sensitivity, and promotes J ‐aggregation, shifting fluorescence into the NIR‐II window for deep‐tissue imaging. The redox conversion also activates photoacoustic signals, enabling responsive tri‐modal imaging (NIR‐II FLI/ ¹⁹ F MRI/PAI). OFBD‐NP shows potent cytotoxicity in vitro under both normoxic and hypoxic conditions via apoptosis. In vivo, it selectively accumulates in tumors, offers high‐contrast imaging, and leads to complete tumor regression in subcutaneous A549 models after laser irradiation, without systemic toxicity. This work demonstrates a smart nanoplatform that integrates deep‐tissue imaging and hypoxia‐triggered therapeutic switching, addressing major limitations of conventional photosensitizers in cancer imaging and phototherapy.