Fenton reaction-independent ferroptosis therapy via glutathione and iron redox couple sequentially triggered lipid peroxide generator.

Abstract

Ferroptosis, a newfound non-apoptotic cell death pathway, results from the accumulation of iron-dependent lipid peroxide (LPO). Recently, emerging iron-based nanomaterials have been extensively developed to induce Fenton reaction-dependent ferroptosis for cancer therapy. However, insufficient amount of H₂O₂ and limited acidity of tumor could not satisfy the optimal conditions for Fenton reaction, which extremely limited the efficacy of ferroptosis therapy. Herein, we report a novel glutathione (GSH) and iron redox couple sequentially triggered LPO generator (LPOgener) which can directly supply the Fenton reaction-independent downstream executioner of ferroptosis for cancer therapy. By harnessing GSH-mediated Fe³⁺ reduction and the well-established iron redox couple-mediated lipid peroxidation, LPOgener was constructed by complete ferric ammonium citrate (FAC) and unsaturated lipids-rich phosphatidylcholine, and formed as FAC loaded liposome. The Fe³⁺ encapsulated in LPOgener could be efficiently reduced to Fe²⁺ under high GSH level in tumor cells. Subsequently, the formed iron redox couple could trigger overwhelming lipid peroxidation for Fenton reaction-independent ferroptosis. Superior anticancer therapeutic effect with little systemic toxicity demonstrated that LPOgener was a potent ferroptosis-inducing agent for cancer therapy. Therefore, to directly supply the druglike, easily prepared, GSH and iron redox couple sequentially triggered LPOgener would provide a new direction in designing strategies for ferroptosis therapy.