FRET-based hypoxia-responsive self-quenching BODIPY nanoparticles enhance lung cancer efficacy while avoiding skin toxicity.

Photodynamic therapy is a promising antitumor modality with significant potential for clinical translation. Given phototoxicity, the development of photosensitizers that exhibit high tumor selectivity continues to be a critical research priority. To suppress the activity of photosensitizers in non-target tissues, a photosensitizer named BDP-Q was designed, comprising a pair of BODIPY derivatives that exhibit intramolecular fluorescence resonance energy transfer (FRET) effects, linked via an azobenzene bond to respond to azoreductase overexpressed in hypoxic tumor microenvironments. BDP-Q displayed nearly complete fluorescence quenching under normal conditions and reducing environment-responsive properties. Furthermore, polyethylene glycol-block-polycaprolactone (PEG-b-PCL) was used to encapsulate BDP-Q to enhance water solubility, thereby facilitating biological applications. BDP-Q nanoparticles (BDP-Q NPs) exhibited over 15.74-fold and 48.47-fold higher ROS production in hypoxic A549 and H226 cells, respectively, compared to normoxic cells, and this effect was inhibited by the azoreductase inhibitor diphenyleneiodonium chloride (DPI). Moreover, BDP-Q NPs demonstrated significant cytotoxicity against A549 cells, having an IC50 of 0.5962 μM in vitro and a 97.6% tumor inhibition rate in vivo. Importantly, unlike conventional photosensitizers, BDP-Q NPs caused no skin damage even under laser irradiation. In summary, this study presents a safe and effective hypoxia-responsive BODIPY-based photosensitizer with significant potential for clinical application.