BackgroundFerroptosis, 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.MethodsTo 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 Fe3+and encapsulated SOR (SOR@TF-Fe3+NVs) were established to synergistically promote ferroptosis, which promoted the iron transport metabolism by TFRC/TF-Fe3+and enhanced SOR efficacy by inhibiting the SLC7A11.ResultsIn vivo and in vitro experiments revealed that SOR@TF-Fe3+NVs predominantly accumulate in the liver, and specifically targeted HCC cells overexpressing TFRC. Various tests demonstrated SOR@TF-Fe3+NVs accelerated Fe3+absorption and transformation in HCC cells. Importantly, SOR@TF-Fe3+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- Fe3+NVs alone.ConclusionsThe present work provides a promising therapeutic strategy for the targeted treatment of HCC.Graphical abstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s40824-023-00401-x.