Brain-Targeting Metal–Organic Framework Nanoplatform Reprogramming Ferroptosis Sensitivity of Glioblastoma

Ferroptosis has emerged as a promising therapeutic approach for the treatment of glioblastoma (GBM). However, the efficacy of ferroptosis is limited by the low expression of acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) in GBM cells, a key enzyme that orchestrates ferroptosis by catalyzing polyunsaturated phospholipid synthesis. Additionally, GBM cells display elevated glutathione (GSH) levels and increased activity of glutathione peroxidase 4 (GPX4), resulting in an antioxidant defense system that suppresses ferroptosis. To overcome these challenges, we designed a metal-organic framework (MOF)-based nanoplatform by coordinating Hf⁴⁺ and Fe³⁺ with a tetrakis(4-carboxyphenyl)porphyrin ligand to enhance ferroptosis. The MOF was loaded with brusatol, a nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor, and surface-modified with a transferrin-tannic acid network to enable blood-brain barrier penetration and active GBM targeting. Upon X-ray irradiation, the high-Z element Hf enhanced radiation deposition, which, in turn, upregulated ACSL4 expression and facilitated phospholipid biosynthesis. Simultaneously, Fe³⁺ released from nanoparticles (NPs) increases the labile iron pool, triggering the Fenton reaction. Meanwhile, brusatol disrupted the Nrf2-GSH-GPX4 axis, suppressing antioxidant defenses and amplifying lipid peroxidation. Consequently, the nanoplatform synergistically induced ferroptosis, effectively suppressing the growth of orthotopic GBM tumors <i>in vivo</i>. Collectively, the MOF-based nanoplatform emerges as a therapeutic strategy for GBM, wherein ferroptosis and the antitumor immune response are synergistically amplified.