Activatable Dual Cancer-Related RNA Imaging and Combined Gene-Chemotherapy through the Target-Induced Intracellular Disassembly of Functionalized DNA Tetrahedron.

Abstract

The desire for a cancer theranostic system with simultaneously accurate diagnosis and efficient therapy is undeniably interminable. Heretofore, theranostic systems with simple components were designed for cancer theranostics but with confined accuracy of diagnosis and side effects of administered drugs. Here, we report an activatable theranostic system for simultaneously imaging dual cancer-related RNAs, mRNA Bcl-2 and piRNA-36026, and combined gene-chemotherapy through the target-induced intracellular disassembly of DNA tetrahedron. Briefly, five customized oligonucleotides are used to assemble the functionalized DNA tetrahedron. The relevant functional nucleic acids, including the antisequence of mRNA Bcl-2, the antisequence of piRNA-36026, and aptamer AS1411, are designed in the customized oligonucleotides with the signal reporters Cy3 and Cy5. Doxorubicin (DOX) is loaded in the functionalized DNA tetrahedron by inlaying between cytosine and guanine to form the activatable cancer theranostic system. The activatable cancer theranostic system is able to recognize MCF-7 cells by aptamer AS1411 and then enter the cells. In the presence of targets, the antisequences in the activatable cancer theranostic system hybridize with intracellular mRNA Bcl-2 and piRNA-36026, leading to the fluorescence signal recovery of Cy3 and Cy5 and the downregulation of two targets in the cytoplasm as well as the consequent apoptosis of MCF-7 cells in the form of gene therapy. Interestingly, as the antisequences are designed in the assembly strands, the hybridization between targets and the antisequences results in the disassembly of the activatable cancer theranostic system and the release of DOX as well as sequential chemotherapy. Advantageously, the activatable cancer theranostic system can achieve imaging of dual cancer-related RNAs with an imaging time window as long as 15 h and exhibit an obvious therapeutic effect in vivo. Therefore, this work is in furtherance of exploration for activatable cancer theranostic systems with high accuracy and efficiency and sheds new light on the development of precision medicine.