Fe(3+)-binding transferrin nanovesicles encapsulating sorafenib induce ferroptosis in hepatocellular carcinoma

BACKGROUND: Ferroptosis, iron-dependent cell death, is an established mechanism for cancer suppression, particularly in hepatocellular carcinoma (HCC). Sorafenib (SOR), a frontline drug for the treatment of HCC, induces ferroptosis by inhibiting the Solute Carrier family 7 member 11 (SLC7A11), with inadequate ferroptosis notably contributing to SOR resistance in tumor cells. METHODS: To further verify the biological targets associated with ferroptosis in HCC, an analysis of the Cancer Genome Atlas (TCGA) database was performed to find a significant co-upregulation of SLC7A11 and transferrin receptor (TFRC), Herein, cell membrane-derived transferrin nanovesicles (TF NVs) coupled with Fe(3+) and encapsulated SOR (SOR@TF-Fe(3+) NVs) were established to synergistically promote ferroptosis, which promoted the iron transport metabolism by TFRC/TF-Fe(3+) and enhanced SOR efficacy by inhibiting the SLC7A11. RESULTS: In vivo and in vitro experiments revealed that SOR@TF-Fe(3+) NVs predominantly accumulate in the liver, and specifically targeted HCC cells overexpressing TFRC. Various tests demonstrated SOR@TF-Fe(3+) NVs accelerated Fe(3+) absorption and transformation in HCC cells. Importantly, SOR@TF-Fe(3+) NVs were more effective in promoting the accumulation of lipid peroxides (LPO), inhibiting tumor proliferation, and prolonging survival rates in HCC mouse model than SOR and TF- Fe(3+) NVs alone. CONCLUSIONS: The present work provides a promising therapeutic strategy for the targeted treatment of HCC. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40824-023-00401-x.