Telomerase-Mediated Self-Assembly of DNA Network in Cancer Cells Enabling Mitochondrial Interference

• Published in: Journal of the American Chemical Society 2023-11, Vol.145 (43), p.23859-23873
• Main Authors: Guo, Yanfei, Li, Siqi, Tong, Zhaobin, Tang, Jianpu, Zhang, Rui, Lv, Zhaoyue, Song, Nachuan, Yang, Dayong, Yao, Chi
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.3c09529

The precise control of the artificially induced reactions inside living cells is emerging as an effective strategy for the regulation of cell functions. Nevertheless, the manipulation of the assembly of exogenous molecules into artificial architectures in response to intracellular-specific signals remains a grand challenge. Herein, we achieve the precise self-assembly of deoxyribonucleic acid (DNA) network inside cancer cells, specifically responding to telomerase, and realize effective mitochondrial interference and the consequent regulation of cellular behaviors. Two functional DNA modules were designed: a mitochondria-targeting branched DNA and a telomerase-responsive linear DNA. Upon uptake by cancer cells, the telomerase primer in linear DNA responded to telomerase, and a strand displacement reaction was triggered by the reverse transcription of telomerase, thus releasing a linker DNA from the linear DNA. The linker DNA afterward hybridized with the branched DNA to form a DNA network on mitochondria. The DNA network interfered with the function of mitochondria, realizing the apoptosis of cancer cells. This system was further administered in a nude mouse tumor model, showing remarkable suppression of tumor growth. We envision that the telomerase-mediated intracellular self-assembly of the DNA network provides a promising route for cancer therapy.