Spatially Asymmetric Nanoparticles for Boosting Ferroptosis in Tumor Therapy

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.