Biomimetic Nanoplatform for Targeted Glioblastoma Therapy via Concurrently Triggering GPX4/DHODH Mediated Ferroptosis

ABSTRACT Glioblastoma multiforme (GBM), the most aggressive and lethal type of brain cancer, is a considerable threat to human health. Conventional therapeutic modalities fail to yield satisfactory outcomes; therefore, a more effective intervention strategy is urgently required. Ferroptosis, a novel type of cell death, has potential for GBM therapy. However, its efficacy is substantially compromised by the tumor‐intrinsic anti‐ferroptosis defense system. Moreover, approaches that trigger ferroptosis by modulating a single target are insufficient. Thus, it is imperative to simultaneously inhibit anti‐ferroptotic regulators to overcome compensatory pathways and achieve robust tumor eradication. Therefore, in the present study, a multifunctional nanoplatform, hollow mesoporous manganese dioxide (H‐MnO ₂ )‐hemin‐leflunomide@membrane ( MHL@M ), is proposed and fabricated. GBM cell membrane coating enables blood‐brain barrier (BBB) penetrating and tumor‐targeting properties. H‐MnO ₂ consumes the overexpressed GSH in the tumor microenvironment (TME), and as derived Mn ²⁺ converts H ₂ O ₂ into more toxic •OH, resulting in a chemodynamic therapy (CDT) effect. Hemin downregulates glutathione peroxidase 4 (GPX4), and leflunomide inhibits dihydroorotate dehydrogenase (DHODH), which synergistically triggers ferroptosis. Both in vitro and in vivo results demonstrate that MHL@M has excellent tumor‐targeting, TME‐responsive, and ferroptosis activation capacities. This study provides a solid foundation for the development of ferroptosis‐based therapeutic strategies for GBM.