Enhanced ferroptosis therapy with a “nano-destructor” by disrupting intracellular redox and iron homeostasis

Ferroptosis is an iron-dependent form of cell death that is also a promising tumor therapeutic modality, however, maintaining redox and iron homeostasis in tumor cells limits the ferroptosis therapeutic effect. Herein, we constructed a GSH-depleting magnetic nanoplatform (D@MOs-P) for enhanced ferroptosis by disruption of redox homeostasis and ferritinophagy-mediated iron disorders. D@MOs-P was constructed by coating disulfide bonds-bridged mesoporous silica shells on magnetic nanoparticles (MNPs) and loaded with dihydroartemisinin (DHA, ROS precursor drug). Upon endocytosis by tumor cells, disulfide bond-mediated glutathione depletion and glutathione peroxidase 4 (GPX4) inactivation will synergize with DHA to disrupt intracellular redox homeostasis. On the other hand, the magnetic hyperthermia generated by D@MOs-P will trigger ferritinophagy to achieve tumor iron dyshomeostasis and enhance ferroptosis. Moreover, the released ferrous ions can activate DHA to produce ROS and further disrupt redox homeostasis. Both in vitro and in vivo results demonstrated that D@MOs-P can significant suppression of tumor growth with minimal side effects through the disturbance of dual homeostasis and the intense ferroptosis of tumor cells. Furthermore, MNPs could also provide excellent T2-weighted MR imaging properties. In this work, magnetic hyperthermia was first proven to trigger autophagy-augmented ferroptosis, and the strategies through multi-pathway intracellular homeostasis disruption described in this article can offer an innovative approach in ferroptosis-based antitumor.