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Glioblastoma (GBM) is one of the deadliest primary brain malignant tumors with a bleak prognosis. Craniotomy surgical resection followed by radiotherapy and chemotherapy was still the standard therapeutic strategy for GBM. As a target alkylating agent, temozolomide (TMZ) was utilized in the therapy of GBM for decades. However, effective treatment for GBM is stymied by rapid acquired resistance and bone marrow suppression. Here, we synthesize a tetrahedral framework nucleic acid (tFNA) nanoparticle that can carry TMZ to enhance the lethality on four GBM cell lines via activating the cell apoptosis and autophagy pathway. Our nanoparticle, namely, tFNA-TMZ, shows a more obvious efficacy in killing TMZ-sensitive cells (A172 and U87) than single-agent TMZ. Besides, tFNA-TMZ was able to attenuate drug resistance in TMZ-resistant cells (T98G and LN-18) via downregulating the expression of O6 …