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.