Phase Separation of Nucleic Acids: Mechanisms, Properties, and Applications

Nucleic acids are essential biological macromolecules bearing genetic information and playing important roles in post-transcriptional regulation. Given their high programmability based on Watson-Crick-Franklin base-pairing interactions, synthetic DNA and RNA oligonucleotides have become versatile building blocks for programmable assembly of nanostructures, nanomachines, and macroscopic materials. Recent discoveries have shown that long-chain nucleic acids can undergo temperature-induced phase separation, enabling rapid and facile formation of micro-sized, nucleic acid-rich condensates. Unlike conventional DNA/RNA nanotechnology, which relies primarily on base-pairing interactions, phase separation leverages the intrinsic polymeric nature of nucleic acids. While it expands the scope of DNA/RNA nanotechnology for new applications, nucleic acid phase separation also provides a fresh perspective for how compartmentalization may have emerged in the prebiotic RNA world during the origin of life. In this Minireview, we discuss the current mechanistic understanding of temperature-induced phase separation of synthetic long-chain DNA and RNA in vitro, in the absence of complex coacervation with proteins and polymers. We highlight strategies for controlling the physical and chemical properties of DNA condensates and review the progress and advances in developing them for various applications.