Metabolic Hijacking: An MOF-Based Nanoprogrammer Overcomes Drug Resistance in Glioblastoma

Glioblastoma (GBM) is one of the deadliest solid cancers with limited treatment options. Resistance to Temozolomide (TMZ), the most common oral anticancer drug available for GBM, develops rapidly and frequently in patients. This study reveals TMZ-sensitive GBM cells rely on glycolysis, while resistant counterparts preferentially utilize fatty acid oxidation (FAO). Hence, we developed an engineered nanoprogrammer using a metal-organic framework (MOF) coloaded with TMZ and the FAO inhibitor (etomoxir, ETO). Postengineered unsaturated Fe³⁺ sites adsorbed transferrin, enabling efficient blood-brain barrier traversal and tumor targeting. TMZ suppressed aggressive tumor growth by eliminating glycolysis-dependent cells during early treatment. Simultaneously, ETO inhibited FAO in resistant cells, forcing metabolic rewiring to glycolysis and restoring TMZ susceptibility. This dual-action strategy disrupted energy pathways in heterogeneous tumors, overcoming resistance. The nanoprogrammer demonstrated potent efficacy in orthotopic and patient-derived drug-resistant GBM models, achieving significant tumor suppression without notable toxicity.