Serum-stable RNA origami nanodevices for sensing and targeting

Serum-stable RNA origami nanodevices for sensing and targeting | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Serum-stable RNA origami nanodevices for sensing and targeting Ebbe Andersen, Emil Kristoffersen, Nikolaj Holck Zwergius, Nestor Sampedro Vallina, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8969222/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Rational RNA design seeks to encode advanced functions in the RNA polymer for applications in medicine and biotechnology. However, current design methods such as RNA origami lack the ability to integrate chemical modifications to improve properties such as increased stability and reduced immunogenicity. Here we demonstrate 2'-fluoro pyrimidine RNA (FY-RNA) origamis that co-transcriptionally fold into well-defined serum-stable nanodevices. Cryogenic electron microscopy reveals how FY-RNA can alter folding pathways and tertiary structure compared to RNA, while molecular dynamics simulations pinpoint the effects from altered hydrogen bonding, sugar pucker, and helix-helix interactions. Despite these structural perturbations, converted RNA fluorogenic aptamers embedded within FY-RNA origami retain partial activity and enable logic-based molecular sensing in human serum. Further, a FY-RNA origami scaffold was designed to aid the structural characterization of an FY-RNA anti-Spike aptamer bound to the Spike protein, resolved to at 3.4 Å resolution, uncovering new fluorine-specific structural motifs and protein interactions. Together, our results establish design principles for nuclease-resistant RNA architectures and position FY-RNA as a versatile polymer for constructing medical nanodevices and environmental sensors. More broadly, this work provides a framework for systematically exploring the folding landscape of chemically modified RNAs, expanding the chemical and functional diversity accessible to nucleic acid nanotechnology and RNA medicine. Biological sciences/Biotechnology/Nanobiotechnology/Nanostructures Physical sciences/Nanoscience and technology/Nanoscale devices/Biosensors Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Video5RNAU98.mp4 Supplementary Video 5. Detail of the MD simulation showing the FU98-Tyr505 interaction. FRNAsupplementaryinformation.pdf Supplementary Information Video4aptamerRBDsim.mp4 Supplementary Video 4. MD simulation of anti-Spike aptamer bound to the RBD. Video6FYRNAFU98.mp4 Supplementary Video 6. Detail of the MD simulation showing the U98-Tyr505 interaction. Video3X90sim.mp4 Supplementary Video 3. MD simulation of the X-90 crossover. Video1PXTsim.mp4 Supplementary Video 1. MD simulation of PXT as RNA and FY-RNA. Video25HTsim.mp4 Supplementary Video 2. MD simulation of 5HT as RNA and FY-RNA. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8969222","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":615236365,"identity":"9f59b34b-445f-4f62-86d3-86cba9af292f","order_by":0,"name":"Ebbe 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