Abstract Chemodynamic therapy (CDT) has shown promising antitumor effects in various malignant tumors. However, its application for glioblastoma (GBM) is significantly hindered by the challenge of delivering CDT agents across the blood‐brain barrier (BBB) and achieving efficient tumor targeting. To overcome these obstacles, this study presents a novel DNA nanomachine (Cu@tFNAs‐G‐A NM) by loading copper ions (Cu 2+ ) onto tetrahedral framework nucleic acids (tFNAs) functionalized with dual DNA aptamers. The dual DNA aptamers (GS24 for BBB penetration and AS1411 for tumor targeting) empowered Cu@tFNAs‐G‐A NM with the ability to effectively penetrate the BBB and selectively accumulate in tumor cells. Upon internalization, the loaded Cu 2+ reacted with tumor‐overexpressed reductive glutathione (GSH) and hydrogen peroxide (H 2 O 2 ), generating hydroxyl radicals (·OH) and inducing tumor cell death. Additionally, Cu@tFNAs‐G‐A NM was found to be rapidly cleared from the brain and normal tissues within 24 h, minimizing potential systemic toxic side effects. These findings demonstrate the promising potential of Cu@tFNAs‐G‐A NM for effective CDT against GBM and open up new avenues for the development of targeted therapies for GBM.

DNA nanomachine‐driven chemodynamic therapy against glioblastoma