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

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Ferroptosis is a promising glioblastoma (GBM) treatment, but its efficacy is limited by low acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) expression and robust antioxidant defenses (glutathione [GSH] and glutathione peroxidase 4 [GPX4]) in GBM cells.
• Developing strategies to overcome these limitations is crucial for effective GBM therapy.

Purpose of the Study:

• To design and evaluate a novel metal-organic framework (MOF)-based nanoplatform for enhanced ferroptosis induction in glioblastoma (GBM).
• To investigate the synergistic effects of X-ray irradiation, iron (Fe³⁺) release, and Nrf2 inhibition on ferroptosis and GBM tumor suppression.

Main Methods:

• A Hf⁴⁺/Fe³⁺-tetrakis(4-carboxyphenyl)porphyrin MOF was synthesized, loaded with brusatol (Nrf2 inhibitor), and surface-modified with transferrin-tannic acid for BBB penetration and GBM targeting.
• The nanoplatform's efficacy was assessed *in vivo* using orthotopic GBM models under X-ray irradiation, monitoring tumor growth, ferroptosis markers, and antioxidant pathways.

Main Results:

• The MOF nanoplatform successfully enhanced X-ray deposition, upregulated ACSL4 expression, and facilitated phospholipid synthesis.
• Fe³⁺ release triggered Fenton reactions, while brusatol inhibited the Nrf2-GSH-GPX4 antioxidant axis, leading to amplified lipid peroxidation.
• The nanoplatform synergistically induced ferroptosis, significantly suppressing orthotopic GBM tumor growth and potentially enhancing antitumor immune responses.

Conclusions:

• The developed MOF-based nanoplatform represents a potent therapeutic strategy for GBM by synergistically enhancing ferroptosis.
• This approach effectively overcomes GBM's intrinsic resistance mechanisms and demonstrates significant *in vivo* antitumor activity.
• The nanoplatform holds promise for advancing GBM treatment by combining ferroptosis induction with immune response modulation.