Frontiers Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (MOE), Institute of Biomolecular and Biomedical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, P. R. China.
J Am Chem Soc. 2022 Mar 16;144(10):4667-4677. doi: 10.1021/jacs.2c00823. Epub 2022 Mar 7.
Constructing artificial dynamic architectures inside cells to rationally interfere with organelles is emerging as an efficient strategy to regulate the behaviors and fate of cells, thus providing new routes for therapeutics. Herein, we develop an intracellular K-mediating dynamic assembly of DNA tetrahedrons inside cells, which realizes efficient mitochondrial interference and consequent regulation on the energy metabolism of living cells. In the designer DNA tetrahedron, one vertex was modified with triphenylphosphine (TPP) for mitochondrial targeting, and the other three vertexes were tethered with guanine-rich sequences that could realize K-mediating formation of intermolecular G-quadruplexes, which consequently led to the assembly of DNA tetrahedrons to form aggregates in the cytoplasm. The DNA aggregates specially targeted mitochondria and served as a polyanionic barrier for substance communication, thus generating a significant inhibition effect on the aerobic respiration function of mitochondria and the associated glycolysis process, which consequently reduced the production of intracellular adenosine triphosphate (ATP). The lack of ATP impeded the formation of lamellipodium that was essential for the movement of cells, consequently resulting in a significant inhibitory effect on cell migration. Remarkably, the migration capacity was suppressed by as high as 50% for cancer cells. This work provides a new strategy for the manipulation of organelles via the endogenous molecule-mediating dynamic assembly of exogenous artificial architectures inside living cells, which is envisioned to have great potential in precise biomedicine.
在细胞内构建人工动态结构以合理干扰细胞器，正成为一种调控细胞行为和命运的有效策略，从而为治疗提供了新途径。在此，我们开发了一种细胞内 K 介导的 DNA 四面体的动态组装，它实现了对线粒体的有效干扰，并对活细胞的能量代谢进行了相应的调控。在设计的 DNA 四面体中，一个顶点用三苯基膦（TPP）修饰以靶向线粒体，另外三个顶点连接有富含鸟嘌呤的序列，这些序列能够实现 K 介导的分子间 G-四链体的形成，从而导致 DNA 四面体组装成细胞质中的聚集体。DNA 聚集体专门靶向线粒体，并作为物质交流的多阴离子屏障，从而对线粒体的需氧呼吸功能和相关的糖酵解过程产生显著的抑制作用，进而减少细胞内三磷酸腺苷（ATP）的产生。缺乏 ATP 会阻碍细胞运动所必需的片状伪足的形成，从而对细胞迁移产生显著的抑制作用。值得注意的是，癌细胞的迁移能力被抑制了高达 50%。这项工作为通过内源性分子介导的活细胞内外源性人工结构的动态组装来操纵细胞器提供了一种新策略，有望在精准医学中具有巨大的潜力。
