NIR-Triggered and ROS-Boosted Nanoplatform for Enhanced Chemo/PDT/PTT Synergistic Therapy of Sorafenib in Hepatocellular Carcinoma

Although being the first-line treatment of advanced hepatocellular carcinoma (HCC), sorafenib (SOR) outcome is limited due to drug resistance and low tumor accumulation. Herein, with MnO(2) as photothermal agent and chlorine6 (Ce6) as photosensitizer, a tumor-targeting and NIR-triggered multifunctional nanoplatform loading sorafenib (MnO(2)-SOR-Ce6@PDA-PEG-FA, MSCPF) was constructed. Owing to oxygen generator MnO(2), MSCPF could generate excessive ROS, thus can alleviate tumor hypoxia and improve sorafenib accumulation in cancer cells. Besides, ROS production further strengthens Ce6-mediated PDT and PDA-mediated PTT. By exploiting these features, MSCPF exhibited excellent antitumor effects on HCC in the in vitro and in vivo studies, compared to solo sorafenib or PDT/PTT treatment. Further mechanism experiments suggested that MSCPF could inhibit P-gp expression and induce ferroptosis via deactivation of GPX4 and SLC7A11, which ultimately enhanced the antitumor efficacy of SOR. In summary, our work highlights a promising NIR-triggered and ROS-boosted nanoplatform for enhanced chemo/PDT/PTT synergistic therapy of SOR in HCC treatment.