A Metal–Phenolic Network Nanoresensitizer Overcoming Glioblastoma Drug Resistance through the Metabolic Adaptive Strategy and Targeting Drug-Tolerant Cells

Glioblastoma (GBM) is the most lethal primary brain tumor with limited therapeutic efficiency because of resistance to Temozolomide (TMZ), which is the standard chemotherapy drug. Here, we developed the metabolic adaptive strategy based on the complex TMZ resistance mechanisms, and engineered metal-phenolic networks (TBFP-MT MPNs) by self-assembly of PEG-polyphenol encapsulating Fe^III, TMZ, and dihydroorotate dehydrogenase (DHODH) inhibitor, modifying T₁₀ and cMBP for blood-brain barrier (BBB) penetration and targeting resistant cells. TBFP-MT suppressed drug efflux by inhibiting mesenchymal epithelial transition (MET) signaling and reduced DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT) by blocking pyrimidine synthesis via DHODH inhibition. Additionally, it triggered ferroptosis by disrupting the DHODH/GPX4 defense systems, overcoming the tumor cell survival mechanisms. In vitro and in vivo studies confirmed its ability to suppress resistant GBM growth and extend survival. This study reveals drug-resistant cell vulnerabilities and provides a new pathway to overcome chemoresistance by disrupting multiple resistance mechanisms in GBM.