Dynamic Assembly of DNA Nanostructures in Living Cells for Mitochondrial Interference

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.