Regulation of Supramolecular Interactions: RNA:DNA Folding and Nanopore Sensing Applications

The intersection of DNA/RNA nanotechnology and single-molecule solid-state nanopore sensing enables precise detection of low-abundance biomolecules. However, a significant challenge persists that nucleic acid molecules readily fold during nanopore translocation, which gives rise to ambiguous current signatures, reduces the number of usable data points, and compromises detection accuracy. Herein, a recent advancement by the Platnich group is highlighted, wherein urea is employed as a noncovalent modulator to participate in the isothermal assembly of MS2 bacteriophage RNA with DNA barcodes. This modulator stably binds to the RNA:DNA hybrids through supramolecular interactions after removal of free urea by buffer exchange. Nanopore assays showed a ≈50% reduction in fold-shift events in the urea-treated group. Atomic force microscopy characterization shows that the persistence length of the hybrids is enhanced by ≈40%. This strategy provides a new noncovalent regulatory tool for nucleic acid nanotechnology and pushes the nanopore sensing technology toward the precision detection of low-abundance RNA.