Despite its effectiveness in eliminating cancer cells, ferroptosis is hindered by the high natural antioxidant glutathione (GSH) levels in the tumor microenvironment. Herein, we developed a spatially asymmetric nanoparticle, Fe3O4@DMS&PDA@MnO2-SRF, for enhanced ferroptosis. It consists of two subunits: Fe3O4 nanoparticles coated with dendritic mesoporous silica (DMS) and PDA@MnO2 (PDA: polydopamine) loaded with sorafenib (SRF). The spatial isolation of the Fe3O4@DMS and PDA@MnO2-SRF subunits enhances the synergistic effect between the GSH-scavengers and ferroptosis-related components. First, the increased exposure of the Fe3O4 subunit enhances the Fenton reaction, leading to increased production of reactive oxygen species. Furthermore, the PDA@MnO2-SRF subunit effectively depletes GSH, thereby inducing ferroptosis by the inactivation of glutathione-dependent peroxidases 4. Moreover, the SRF blocks Xc- transport in tumor cells, augmenting GSH depletion capabilities. The dual GSH depletion of the Fe3O4@DMS&PDA@MnO2-SRF significantly weakens the antioxidative system, boosting the chemodynamic performance and leading to increased ferroptosis of tumor cells.
Keywords: Janus; core@shell; ferroptosis; nanoparticle; porous materials.