Arsenic-Loaded Biomimetic Iron Oxide Nanoparticles for Enhanced Ferroptosis-Inducing Therapy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) has a poor response to most available systemic therapies due to intrinsic or acquired resistance to apoptosis. Ferroptosis-based therapy is expected to circumvent those limitations. Therefore, the rational design of ferroptosis-based therapies with targeted delivery of ferroptosis inducers for HCC is in need. In this study, we found that arsenic trioxide (ATO) can efficiently induce ferroptosis in HCC cells, and this effect could be reversed by the iron chelator deferoxamine. On this basis, a drug delivery system was constructed to enhance the therapeutic efficacy of ATO by camouflaging ATO-loaded magnetic nanoparticles (Fe3O4) with HCC cell membranes, termed AFN@CM. After AFN@CM treatment, glutathione peroxidase 4 was strongly inhibited and intracellular lipid peroxide species were significantly increased in HCC cells. In addition, enhanced ferroptosis and tumor suppression were observed both in vitro and in vivo. The bio-safety of AFN@CM was also demonstrated by the in vivo toxicity evaluation. In addition, benefiting from the cell membrane coating, AFN@CM showed enhanced accumulation at tumor sites and achieved continuous tumor elimination in the mouse model. In conclusion, AFN@CM exhibited satisfactory therapeutic efficacy in the treatment of HCC and provided a desirable ferroptosis-based strategy for safe and reliable HCC therapeutics.