Spatiotemporally tumor ferritin disruption enhances sorafenib induced ferroptosis in hepatocellular carcinoma

• The regulation of ferritin was achieved via the spatiotemporal ADV-UTMD technique. • Tumor cell ferroptosis was successfully induced via ferritin disruption. • The iron pool disruption improved the treatment of sorafenib-insensitive HCC . Sorafenib (Sor), a first-line drug for advanced hepatocellular carcinoma (HCC), can potently induce tumor ferroptosis by inhibiting the cystine/glutamate countertransporter (System Xc-). However, tumors can upregulate the expression of ferritin to prevent its progression to ferroptosis , which induces Sor insensitivity. In this study, ultrasound (US) reaction nanoparticles (NPs) composed of ferritin-homing peptide (HKN 15 )-modified poly (lactic-coglycolic acid) and the acoustic droplet vaporization (ADV)-responsive material perfluorhexane (PFH) were fabricated. Owing to the positive feedback effects of HKN 15 and ferritin overexpression, the NPs (HKN 15 @PLGA-PFH) specifically accumulate around ferritin in HCC cells. With US irradiation at pathological regions, the spatiotemporally ADV effect can influence the stability of the iron pool named ferritin, which releases cellular iron, leading to inevitable ferroptosis through the production of ROS and lipid peroxidation and a reduction in GSH and GPx4. Overall, the cytotoxic effect of the combined treatment group was 1.6 times greater than that of the Sor-only group against HCC cells, which highlights an innovative potential strategy for increasing the therapeutic efficacy of Sor through combined treatment to sensitize HCC cells to ferroptosis.