Synthetic nucleic-acid droplets: a bioprogramming platform for designer microliquids

H Udono and T Maruyama and NN Evangelista and N Yoshida and Y Aizaki and K Goraku and K Takagi and R Hasegawa and M Takinoue, POLYMER JOURNAL, 57, 845-862 (2025).

DOI: 10.1038/s41428-025-01050-8

Research on biomolecular liquid-state condensates (droplets) in cells has sparked burgeoning interest among synthetic biologists in programmable droplets assembled from synthetic nucleic acids-- information-encoding biomolecules amenable to facile synthesis, versatile sequence design, and molecular decoration. Analogous to biological condensates, well-engineered nanostructures consisting of DNA or RNA strands, which are negatively charged, phase-separate into membrane-free droplets via weak multivalent specific interactions or via electrostatic attraction with positively charged peptides. The membraneless compartments of these droplets allow stimuli responsiveness to molecular cues (DNA/RNA, enzymes, etc.). Nucleic acid droplets thus offer a powerful platform for programming their various features, including hierarchical structuring, molecular recognition capabilities, droplet interactions, and physical properties. Specifically, we describe a DNA linker that serves as a programmable surfactant bridging immiscible DNA phases, which, upon molecular inputs, alters their separation level from mixed to divided states. Furthermore, a rational combination of these features can create intelligent liquid-state architectures capable of naturally unachievable functions and dynamics, such as Boolean operations and directional motion. To predict how molecular-level encoding leads to macroscopic characteristics, coarse- grained models, which treat nucleic acids as strings of interacting rigid beads, are widely utilized. This emerging field represents a cross-disciplinary integration of various fields, from biophysics to information science. This Focus Review highlights recent advances in synthetic nucleic-acid droplets and their far-reaching potential, concluding with perspectives on their future directions and challenges.

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