Synthetic vectors for activating the driving axis of ferroptosis.

Abstract

Ferroptosis is a promising strategy for cancer therapy, with numerous inhibitors of its braking axes under investigation as potential drugs. However, few studies have explored the potential of activating the driving axes to induce ferroptosis. Herein, phosphatidylcholine peroxide decorating liposomes (LIP_PCPO) are synthesized to induce ferroptosis by targeting divalent metal transporter 1 (DMT1). LIP_PCPO is found to boost lysosomal Fe²⁺ efflux by inducing cysteinylation of lysosomal DMT1, resulting in glutathione peroxidase 4 (GPX4) suppression, glutathione depletion and ferroptosis in breast cancer cells and xenografts. Importantly, LIP_PCPO induced ferroptotic cell death is independent of acquired resistance to radiation, chemotherapy, or targeted agents in 11 cancer cell lines. Furthermore, a strong synergistic ferroptosis effect is observed between LIP_PCPO and an FDA-approved drug, artesunate, as well as X rays. The formula of LIP_PCPO encapsulating artesunate significantly inhibits tumor growth and metastasis and improves the survival rate of breast cancer-bearing female mice. These findings provide a distinct strategy for inducing ferroptosis and highlight the potential of LIP_PCPO as a vector to synergize the therapeutic effects of conventional ferroptosis inducers.