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

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 ¹⁹F 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/¹⁹F 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.