Tumor Microenvironment-Responsive One-for-All Molecular-Engineered Nanoplatform Enables NIR-II Fluorescence Imaging-Guided Combinational Cancer Therapy.

The activable NIR-based phototheranostic nanoplatform (NP) is considered an efficient and reliable tumor treatment due to its strong targeting ability, flexible controllability, minimal side effects, and ideal therapeutic effect. This work describes the rational design of a second near-infrared (NIR-II) fluorescence imaging-guided organic phototheranostic NP (FTEP-TBFc NP). The molecular-engineered phototheranostic NP has a sensitive response to glutathione (GSH), generating hydrogen sulfide (H2S) gas, and delivering ferrocene molecules in the tumor microenvironment (TME). Under 808 nm irradiation, FTEP-TBFc could not only simultaneously generate fluorescence, heat, and singlet oxygen but also greatly enhance the generation of reactive oxygen species to improve chemodynamic therapy (CDT) and photodynamic therapy (PDT) at a biosafe laser power of 0.33 W/cm2. H2S inhibits the activity of catalase and cytochrome c oxidase (COX IV) to cause the enhancement of CDT and hypothermal photothermal therapy (HPTT). Moreover, the decreased intracellular GSH concentration further increases CDT's efficacy and downregulates glutathione peroxidase 4 (GPX4) for the accumulation of lipid hydroperoxides, thus causing the ferroptosis process. Collectively, FTEP-TBFc NPs show great potential as a versatile and efficient NP for specific tumor imaging-guided multimodal cancer therapy. This unique strategy provides new perspectives and methods for designing and applying activable biomedical phototheranostics.