Trisulfide Bond‐Mediated Molecular Phototheranostic Platform for “Activatable” NIR‐II Imaging‐Guided Enhanced Gas/Chemo‐Hypothermal Photothermal Therapy

Abstract Tumor microenvironment (TME)‐triggered phototheranostic platform offers a feasible strategy to improve cancer diagnosis accuracy and minimize treatment side effects. Developing a stable and biocompatible molecular phototheranostic platform for TME‐activated second near‐infrared (NIR‐II) fluorescence imaging‐guided multimodal cascade therapy is a promising strategy for creating desirable anticancer agents. Herein, a new NIR‐II fluorescence imaging‐guided activatable molecular phototheranostic platform (IR‐FEP‐RGD‐S‐S‐S‐Fc) is presented for actively targeted tumor imaging and hydrogen sulfide (H 2 S) gas‐enhanced chemodynamic‐hypothermal photothermal combined therapy (CDT/HPTT). It is revealed for the first time that the coupling distance between IR‐FE and ferrocene is proportional to the photoinduced electron transfer (PET), and the aqueous environment is favorable for PET generation. The part of Cyclic‐RGDfK (cRGDfk) peptides can target the tumor and benefit the endocytosis of nanoparticles. The high‐concentration glutathione (GSH) in the TME will separate the fluorescence molecule and ferrocene by the GSH‐sensitive trisulfide bond, realizing light‐up NIR‐II fluorescence imaging and a cascade of trimodal synergistic CDT/HPTT/gas therapy (GT). In addition, the accumulation of hydroxyl radicals (•OH) and down‐regulation of glutathione peroxidase 4 (GPX4) can produce excessive harmful lipid hydroperoxides, ultimately leading to ferroptosis.