Yasuda Soshu, Morihiro Kunihiko, Koga Shuichiro, Okamoto Akimitsu
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Angew Chem Int Ed Engl. 2025 Apr 7;64(15):e202424421. doi: 10.1002/anie.202424421. Epub 2025 Feb 11.
DNA decoys inhibit cellular transcription factors and 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 nuclear factor kappa B (NF-κB), whose overexpression is related to many diseases, including cancer. The transformation of the DNA hairpin pair to the NF-κB DNA decoy was catalyzed by miR-21, which is expressed in various types of cancers. Intracellular CHA progression and the inhibitory effect against NF-κB were observed only in miR-21 overexpressing cancer cells. The intracellular miR-21-catalyzed production of the NF-κB DNA decoy has the potential to reduce side effects on normal cells, thereby strengthening the therapeutic profile of the CHA-decoy system. 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.
DNA诱饵可抑制细胞转录因子，有望成为用于下调转录过程的核酸药物之一。然而，在空间上控制DNA诱饵的开/关功效以避免对正常细胞产生副作用具有挑战性。为了减少正常细胞中不必要的诱饵功能，我们采用催化发夹组装（CHA）技术，使其在特定微RNA（miRNA）的作用下，由一对发夹DNA产生DNA双链体。我们设计了DNA发夹对，使其形成与核因子κB（NF-κB）结合的DNA诱饵，NF-κB的过表达与包括癌症在内的多种疾病相关。DNA发夹对向NF-κB DNA诱饵的转化由在各种类型癌症中均有表达的miR-21催化。仅在miR-21过表达的癌细胞中观察到细胞内CHA进程及对NF-κB的抑制作用。细胞内miR-21催化产生NF-κB DNA诱饵有潜力减少对正常细胞的副作用，从而增强CHA-诱饵系统的治疗效果。定制催化性miRNA与靶转录因子组合的能力将使我们的技术成为针对包括癌症在内的多种疑难疾病的“个性化药物发现系统”。
