Glutathione- responsive Phototheranostic platform for imaging-guided enhanced oxidation photoimmunotherapy-ferroptosis synergistic hepatocellular carcinoma therapy.

Phototheranostics have emerged as a promising approach in precision medicine. However, the poor tumor selectivity of photosensitizers, insufficient oxidative stress and the intrinsic antioxidant system of tumors compromise the efficacy of phototherapeutic strategies. In this study, we designed a novel phototheranostic platform (ICP@SRF-GPC3 NPs) for active tumor-targeted imaging and oxidation-enhanced photoimmunotherapy-ferroptosis combined therapy. The ICP@SRF-GPC3 NPs were fabricated by conjugating near-infrared photosensitizer IR780 with cystine-polyethylene glycol, modifying it with the Glypican-3 monoclonal antibody and encapsulating of the ferroptosis inducer sorafenib (SRF). ICP@SRF-GPC3 NPs with improved water solubility and liver tumor specificity can produce reactive oxygen species (ROS) upon 808 nm laser irradiation and enable photoimmunotherapy-mediated oxidation treatment. In the tumor microenvironment, the high concentration of glutathione (GSH) cleaved the linkage between the IR780 and the cystine moiety, realizing superior near-infrared fluorescence imaging and synergistic photoimmunotherapy-ferroptosis therapy. The released SRF inhibited cystine/glutamate antiporter, thereby blocking cystine uptake in tumor cells and suppressing GSH synthesis. By depleting existing GSH reserves while simultaneously inhibiting its biosynthetic pathway, ICP@SRF-GPC3 NPs effectively exhausted intracellular GSH, weakening the anti-oxidation ability of tumor cells and amplifying oxidative stress. In a BALB/c nude mouse model bearing GPC3-overexpressing Hepa1-6 allografts, the combination of photoimmunotherapy with ferroptosis not only effectively suppressed primary tumor growth through amplified ROS generation, but also promoted damage-associated molecular patterns release, thereby eliciting a robust immune response that eliminated metastatic and distant tumors. Overall, ICP@SRF-GPC3 NPs offers a promising strategy for regulating GSH and ROS levels in synergistic photoimmunotherapy-ferroptosis antitumor therapy, which has potential clinical applications.