Self-engineered lipid peroxidation nano-amplifier for ferroptosis-driven antitumor therapy

Ferroptosis has been extensively explored as a promising therapeutic target for cancer. Most ferroptosis inducers promote the intracellular accumulation of lipid peroxidation by depleting glutathione peroxidase 4 (GPX4). However, GPX4 suppression alone is not sufficient to trigger intracellular lipid peroxidation storm, resulting in inefficient ferroptosis induction and unsatisfactory antitumor effect. Herein, we precisely engineer a lipid peroxidation nano-amplifier based on a facile drug-deliver-drug (DDD) engineering strategy. Interestingly, FIN56 (a GPX4 inhibitor) is found to readily co-assemble with arachidonic acid (AA) into stable nanoparticles without the assistance of any excipients. Then, a disulfide bond-containing amphipathic PEG polymer is decorated on the nano-amplifier for long blood circulation and tumor-specific drug release. Notably, AA could not only be converted into abundant lipid reactive oxygen species (ROS) but also elicit membranous lipid peroxidation in tumor cells, synergistically inducing tumor ferroptosis with FIN56-mediated GPX4 depletion. As expected, the nano-amplifier exhibits potent ferroptosis-driven antitumor activity in 4 T1 breast tumor-bearing mice. This study drives a conceptual step forward in ferroptosis-driven nanotherapeutics, and offers a novel DDD co-delivery paradigm for combination cancer therapy.