Fe3+-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 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.

Results: In 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.

Conclusions: The present work provides a promising therapeutic strategy for the targeted treatment of HCC.