An Intelligent Nanoplatform for Orthotopic Glioblastoma Therapy by Nonferrous Ferroptosis

Abstract Ferroptosis, characterized by iron accumulation and lipid peroxidation (LPO), can avoid the intrinsic apoptotic resistance of tumor cells and have been explored for glioblastoma (GBM) therapy. However, the direct delivery of iron species may trigger severe adverse side effects. Using nonferrous species to induce LPO‐mediated ferroptosis maybe a promising strategy for GBM treatment, but there is still no report till now. Therefore, in this study, first an intelligent blood–brain barrier (BBB)‐permeable nanoplatform (PCN‐224@Au/CeO₂‐Lf) is constructed for efficient nonferrous ferroptosis‐involved orthotopic GBM therapy. Porous coordination network‐224 nanoparticles (PCN‐224 NPs) are served as sonosensitizers for sonodynamic therapy (SDT). In situ growth of small Au NPs with glucose oxidase (GOx)‐mimic activity and CeO₂ NPs with peroxidase (POD)‐ and catalase (CAT)‐mimic abilities are applied for H₂O₂ self‐supplement, more acidic microenvironment, and generation of cytotoxic hydroxyl radical (·OH) and O₂, which improves the efficacy of SDT. Besides, Ce⁴⁺‐mediated glutathione (GSH) depletion further promotes ferroptosis and apoptosis. Reactive oxygen species (ROS) burst and GSH consumption‐related glutathione peroxidase 4 (GPX4) deactivation promote the accumulation of LPO, leading to significant nonferrous ferroptosis, which can effectively shrink the orthotopic GBM. These findings first demonstrate the nonferrous ferroptosis strategy for efficient GBM treatment.