Amplified Production of a DNA Decoy Catalyzed by Intracellular MicroRNA

Abstract

DNA decoys are expected to be among the nucleic acid drugs used to downregulate the transcription process. However, spatially controlling the on/off efficacy of DNA decoys to avoid side effects on normal cells is challenging. To reduce undesired decoy function in normal cells, we adopted catalytic hairpin assembly (CHA) to produce a DNA duplex from a hairpin DNA pair in response to a specific microRNA (miRNA). We designed the DNA hairpin pairs to form a DNA decoy that binds to NF-kB, whose overexpression is related to many diseases, including cancer. The transformation of the DNA hairpin pair to the NF-kB DNA decoy was catalyzed by miR-21. Intracellular CHA progression and the inhibitory effect against NF-kB were observed only in miR-21 overexpressing cancer cells. The intracellular miR-21-catalyzed production of the NF-kB DNA decoy has the potential to reduce side effects on normal cells, thereby strengthening the therapeutic profile of the CHA-decoy system. This study is the first to use the CHA product itself as a selective therapeutic substance. The ability to customize the combination of catalytic miRNA and target transcription factors would allow our technology to serve as a “personalized drug discovery system” for a variety of challenging diseases, including cancer.