biostudies-literatureSchmidt TTEuropean Research CouncilEuropean Union under the Horizon 2020 Program, FET- Open: DNA-FAIRYLIGHTS,Training in Sensor Technologies for a Healthy and Sustainable FutureEPSRCEPSRC NanoDTC CambridgeUK Research and InnovationEngineering and Physical Sciences Research Councile202508917https://www.ebi.ac.uk/biostudies/studies/S-EPMC12582014biostudies-literatureUnknown64(45)DNA and RNA nanotechnology enables the precise assembly of molecular architectures, with applications in bioengineering, supramolecular chemistry, and sensing. The material properties of these biopolymers can be adjusted covalently or, more simply, through non-covalent interactions with small molecules. Herein, we demonstrate the use of urea, an abundant and inexpensive small molecule, to modulate the stiffness of RNA:DNA hybrid nanostructures. Our results suggest that supramolecular interactions between urea and the A-form-like helix rigidify the hybrid polymers, as evidenced by both solid-state nanopore measurements and atomic force microscopy. Nanopore sensing reveals that preparing topologically-barcoded RNA:DNA hybrids in urea results in a 50% reduction in folded translocations. This Angewandte Chemie (International ed. in English)Supramolecular Interactions Modulate RNA:DNA Folding Observed via Nanopore Sensing.PMC12582014EP/X023311/1964995EP/S022953/1EP/S023046/1883703EP/X037770/1Li YBaumberg JJAlexii REKeyser UFSchmidt TTEarle MKPatino-Guillen GPlatnich CMfalseSupramolecular Interactions Modulate RNA:DNA Folding Observed via Nanopore Sensing.DNA and RNA nanotechnology enables the precise assembly of molecular architectures, with applications in bioengineering, supramolecular chemistry, and sensing. The material properties of these biopolymers can be adjusted covalently or, more simply, through non-covalent interactions with small molecules. Herein, we demonstrate the use of urea, an abundant and inexpensive small molecule, to modulate the stiffness of RNA:DNA hybrid nanostructures. Our results suggest that supramolecular interactions between urea and the A-form-like helix rigidify the hybrid polymers, as evidenced by both solid-state nanopore measurements and atomic force microscopy. Nanopore sensing reveals that preparing topologically-barcoded RNA:DNA hybrids in urea results in a 50% reduction in folded translocations. This 2025-01-01T00:00:00Z2025 Nov2026-06-05T11:34:53.162Z2026-05-16T03:13:12.716ZS-EPMC125820144094460010.1002/anie.202508917