Self-assembling sugars as synthetic capsids

Self-assembling sugars as synthetic capsids | 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 Physical Sciences - Article Self-assembling sugars as synthetic capsids Matthieu Sollogoub, Léonid Lavnevich, Pierre Evenou, Rebecca Churamani, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7528470/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 All living organisms, from the simplest bacteria to complex multicellular life forms, rely on a common set of molecular building blocks: lipids, nucleic acids, proteins, and saccharides, that orchestrate cellular structure, function, and replication. These molecules operate within defined functional boundaries, a principle also mirrored in viral architectures that exploit host biochemistry using the same building blocks. In viruses, proteins and lipids typically package and protect nucleic acids,4,6 a strategy that is emulated in synthetic systems for gene delivery and vaccine design. Synthetic proteins have been designed to mimic viral capsid proteins, successfully encapsulating double-stranded nucleic acid and protecting it from nuclease degradation.8 Smaller oligopeptides also successfully embedded nucleic acid but have yet to demonstrate protective activity.11 While small molecules can form rod-like assemblies with nucleic acids, they do not achieve true capsid-like encapsulation.12-18 Here we show that a specially designed saccharidic molecule, a self-assembling cyclodextrin (CD), can encapsulate oligonucleotides into linear, virus-like fibres with protective functionality.22 The co-assembly we report comprises nanometre-scale tubular fibres of seven CD-based protofibrils that encapsulate oligonucleotides. A cryo-EM structure at 3.3 Å resolution unveils the intricate details of this co-assembly at the molecular scale. Molecular dynamics simulations and statistical mechanical calculations reveal that structural adaptability, rather than fully ordered packing, drives the cooperative self-assembly with entropy playing a pivotal role in stabilizing the fibre architecture. Unlike conventional capsids that rely on uniformity and tight packing, our system benefits from disorder arising via gaps in oligonucleotide packing as well as bending fluctuations that promote stable encapsulation. This study introduces a novel paradigm in molecular design, where sugars replace proteins and entropic contributions enhance, rather than disrupt, multi-component self-assembly. These results broaden the functional repertoire of saccharides in molecular engineering and open new avenues for non-viral gene delivery systems, potentially leading to better customizable and biocompatible therapeutic platforms. Physical sciences/Chemistry/Supramolecular chemistry/Supramolecular polymers Physical sciences/Chemistry/Supramolecular chemistry/Self-assembly Biological sciences/Structural biology/Electron microscopy/Cryoelectron microscopy Full Text Additional Declarations Yes there is potential Competing Interest. P.A.D. and R.C. are current or former Sanofi employees and may hold shares and/or stock options in the company. Supplementary Files SupplementaryInformation.pdf Self-assembling sugars as synthetic capsids 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-7528470","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Physical Sciences - Article","associatedPublications":[],"authors":[{"id":532208695,"identity":"1ee361e2-dbf2-47d9-bfc7-bd4ffe100bce","order_by":0,"name":"Matthieu Sollogoub","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABbklEQVRIie3PPUvDQBgH8AuBdrma9UI130A4CaQKRb9KQqFTxI4ZaggE4lLsWlG/g5M4ODwhkC4nXQvNEAl0EyIdFfXyVivYXTD/4Z7cyy/PHUJ16vzRiIjmVYA4K0QEPkK1S/Ixm0prILglQaDnZxr6L4TPZWeDoB8E001S7a3J/sVsmgwGXcORAgDdOlfoYrRKXx8jpdN2QWw9HBrj9vQ5SC1EOrnRWE9wJ7RvOKSvg86mKo2e7uXJcqke3YS62GLEuLo0KQBDZDdvrQEnmAacYAqGFxp389N7EUPAP8zOW8sjKmUYge8hu3iWNksy8skvxipiJquCnKViRk5YMwb/A5GSzPMuYDjIzMgwI6hddkEZUShGFHznmyQH15j2VK94C6hyFGryBJYqnfepcMsJYfyfLCQVmRnxCr8f742lwI9Ty1Z2Fm6SphApdN6L0YtnY2nUTFJr2C3JOo2iBGhryJZ1ezupU6dOnX+bLwZeoE8ZKR1CAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-0500-5946","institution":"Sorbonne Université","correspondingAuthor":true,"prefix":"","firstName":"Matthieu","middleName":"","lastName":"Sollogoub","suffix":""},{"id":532208696,"identity":"05f10361-e0a3-43d1-87b7-7298df94acc9","order_by":1,"name":"Léonid Lavnevich","email":"","orcid":"","institution":"Sorbonne Université","correspondingAuthor":false,"prefix":"","firstName":"Léonid","middleName":"","lastName":"Lavnevich","suffix":""},{"id":532208697,"identity":"512f3f11-753d-4774-8155-b19eab898c20","order_by":2,"name":"Pierre Evenou","email":"","orcid":"","institution":"Sorbonne Université","correspondingAuthor":false,"prefix":"","firstName":"Pierre","middleName":"","lastName":"Evenou","suffix":""},{"id":532208698,"identity":"c55eca30-4acd-434f-b5d0-0694b3df3f39","order_by":3,"name":"Rebecca Churamani","email":"","orcid":"","institution":"Sorbonne Université","correspondingAuthor":false,"prefix":"","firstName":"Rebecca","middleName":"","lastName":"Churamani","suffix":""},{"id":532208699,"identity":"40825383-94b5-4d3d-b63d-a0519ae24c4a","order_by":4,"name":"Rafael Veloso","email":"","orcid":"","institution":"Sorbonne Université","correspondingAuthor":false,"prefix":"","firstName":"Rafael","middleName":"","lastName":"Veloso","suffix":""},{"id":532208700,"identity":"04261a44-dfb7-432a-98e4-58e0c65d9b3c","order_by":5,"name":"Carlos Fernandes","email":"","orcid":"","institution":"Sorbonne Université","correspondingAuthor":false,"prefix":"","firstName":"Carlos","middleName":"","lastName":"Fernandes","suffix":""},{"id":532208701,"identity":"6095bd75-7649-4d6b-8ef6-3a59129a4c8a","order_by":6,"name":"Charline Fagnen","email":"","orcid":"","institution":"Sorbonne Université","correspondingAuthor":false,"prefix":"","firstName":"Charline","middleName":"","lastName":"Fagnen","suffix":""},{"id":532208702,"identity":"697e4a74-556c-4269-9a40-4cbffa1de974","order_by":7,"name":"Valérian Libérioux","email":"","orcid":"","institution":"Sorbonne Université","correspondingAuthor":false,"prefix":"","firstName":"Valérian","middleName":"","lastName":"Libérioux","suffix":""},{"id":532208703,"identity":"fb9d3a3b-0401-430a-990d-e56f89e15bcb","order_by":8,"name":"Dmitri Colesnic","email":"","orcid":"","institution":"Sorbonne Université","correspondingAuthor":false,"prefix":"","firstName":"Dmitri","middleName":"","lastName":"Colesnic","suffix":""},{"id":532208704,"identity":"17d8a573-7dfd-4eba-be79-459af95fbd80","order_by":9,"name":"Jean-Michel Guigner","email":"","orcid":"","institution":"IMPMC Sorbonne university","correspondingAuthor":false,"prefix":"","firstName":"Jean-Michel","middleName":"","lastName":"Guigner","suffix":""},{"id":532208705,"identity":"ca990770-a34e-42f1-9c2c-d16a4f048815","order_by":10,"name":"Pierre-Alexandre Driguez","email":"","orcid":"","institution":"Sanofi","correspondingAuthor":false,"prefix":"","firstName":"Pierre-Alexandre","middleName":"","lastName":"Driguez","suffix":""},{"id":532208706,"identity":"ce2d51ef-4ca1-44b2-af89-0f65809ff61f","order_by":11,"name":"Sylvain Engilberge","email":"","orcid":"https://orcid.org/0000-0001-8680-6790","institution":"Univ. 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These molecules operate within defined functional boundaries, a principle also mirrored in viral architectures that exploit host biochemistry using the same building blocks. In viruses, proteins and lipids typically package and protect nucleic acids,4,6 a strategy that is emulated in synthetic systems for gene delivery and vaccine design. 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Molecular dynamics simulations and statistical mechanical calculations reveal that structural adaptability, rather than fully ordered packing, drives the cooperative self-assembly with entropy playing a pivotal role in stabilizing the fibre architecture. Unlike conventional capsids that rely on uniformity and tight packing, our system benefits from disorder arising via gaps in oligonucleotide packing as well as bending fluctuations that promote stable encapsulation. This study introduces a novel paradigm in molecular design, where sugars replace proteins and entropic contributions enhance, rather than disrupt, multi-component self-assembly. These results broaden the functional repertoire of saccharides in molecular engineering and open new avenues for non-viral gene delivery systems, potentially leading to better customizable and biocompatible therapeutic platforms.","manuscriptTitle":"Self-assembling sugars as synthetic capsids","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-19 05:24:57","doi":"10.21203/rs.3.rs-7528470/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4283c7e7-83bd-4304-88bd-fdc4a3e1b6a7","owner":[],"postedDate":"December 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":56571018,"name":"Physical sciences/Chemistry/Supramolecular chemistry/Supramolecular polymers"},{"id":56571019,"name":"Physical sciences/Chemistry/Supramolecular chemistry/Self-assembly"},{"id":56571020,"name":"Biological sciences/Structural biology/Electron microscopy/Cryoelectron microscopy"}],"tags":[],"updatedAt":"2025-12-19T05:24:57+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-19 05:24:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7528470","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7528470","identity":"rs-7528470","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}