Deformable Smart DNA Nanomachine for Synergistic Intracellular Cancer‐Related miRNAs Imaging and Chemo‐Gene Therapy of Drug‐Resistant Tumors

Abstract Diagnosis and treatment of tumor especially drug‐resistant tumor remains a huge challenge, which requires intelligent nanomedicines with low toxic side effects and high efficacy. Herein, deformable smart DNA nanomachines are developed for synergistic intracellular cancer‐related miRNAs imaging and chemo‐gene therapy of drug‐resistant tumors. The tetrahedral DNA framework (MA‐TDNA) with fluorescence quenched component and five antennas is self‐assembled first, and then DOX molecules are loaded on the MA‐TDNAs followed by linking MUC1‐aptamer and Mcl‐1 siRNA to the antennas of MA‐TDNA, so that the apt‐MA‐TDNA@DOX‐siRNA (DNA nanomachines) is constructed. The DNA nanomachine can respond to two tumor‐related miRNAs in vitro and in vivo, which can undergo intelligent miRNA‐triggered opening of the framework, resulting in the “turn on” of the fluorescence for sensitively and specifically sensing intracellular miRNAs. Meanwhile, both miRNA‐responded rapid release and pH‐responded release of DOX are achieved for chemotherapy of tumor. In addition, the gene therapy of the DNA nanomachines is achieved due to the miRNA‐specific capture and the RNase H triggered release of Mcl‐1 siRNA. The DNA nanomachines intergrading both tumor imaging and chemo‐gene therapy in single nanostructures realized efficient tumor‐targeted, image‐guided, and microenvironment‐responsive tumor diagnosis and treatment, which provides a synergetic antitumor effect on drug‐resistant tumor.