Highly selective and effective ferroptosis liposomal nanodrugs for synergistic antitumor therapy

Ferroptosis is a recently discovered emerging regulated cell death pattern characterized by iron-dependent lipid peroxidation and has enormous potential in tumor therapy. However, the antioxidant defense system during tumor cell metabolism hampers the ferroptosis-mediated anticancer effect, especially the GSH/GPX4 pathway, which is regarded as the classic means of scavenging excessive lipid peroxidation production. Here, we developed an iron-based nanodrug (ipFFR) with efficient Fenton catalytic activity and encapsulated the ferroptosis inducer RSL3. This formulation consists of Fe@Fe3O4 nanoparticles and RSL3, encapsulated in nanoliposomes containing DSPE-PEG-iRGD for precise tumor-targeted delivery of ipFFR. The ultrasmall Fe@Fe3O4 metal nanoparticles were enabled to catalyze endogenous H2O2 and produce toxic •OH under weakly acidic condition and were then quickly excreted from the body. Furthermore, the released ferroptosis inducer RSL3 specifically inhibited the activity of glutathione peroxidase 4 (GPX4) to block the antioxidant pathway of ferroptosis, synergizing and thereby enhancing ferroptosis therapy. This study may open up new avenues in designing nanomedicines with synergistic effects to enhance ferroptosis therapy.