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

Résumé fourni par la source

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 Hf 4 + and Fe 3 + 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, Fe 3 + 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 in vivo . Collectively, the MOF-based nanoplatform emerges as a therapeutic strategy for GBM, wherein ferroptosis and the antitumor immune response are synergistically amplified.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.