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

## TL;DR

A new fluorinated nanoemulsion enables deep-tissue imaging and adaptive phototherapy for lung cancer by switching between therapies based on tumor oxygen levels.

## Contribution

A fluorinated aza-BODIPY nanoemulsion that enables hypoxia-responsive, multimodal imaging-guided phototherapy with switchable PDT/PTT.

## Key findings

- The nanoemulsion shows potent cytotoxicity in vitro under both normoxic and hypoxic conditions.
- In vivo, it achieves complete tumor regression in A549 models without systemic toxicity.
- The platform enables tri-modal imaging (NIR-II FLI/19F MRI/PAI) for real-time monitoring of therapy.

## 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 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.

Fluorinated N‐oxide aza‐BODIPY nanoemulsions integrate fluorination‐driven molecular design with co‐assembly in fluorinated oil for multimodal imaging‐guided phototherapy. The co‐assembly redshifts fluorescence into the NIR‐II window for deep‐tissue imaging and provides a unified 19F signal for background‐free, quantitative MRI. Under hypoxia, intracellular reduction switches photodynamic therapy to photothermal therapy and activates photoacoustic signals, achieving tri‐modal imaging‐guided adaptive phototherapy for efficient tumor regression.