Nanoscale domains govern local diffusion and aging within FUS condensates

Nanoscale domains govern local diffusion and aging within FUS condensates | 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 Nanoscale domains govern local diffusion and aging within FUS condensates Nils Walter, Guoming Gao, Emily Sumrall This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6406576/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Nov, 2025 Read the published version in Nature Nanotechnology → Version 1 posted You are reading this latest preprint version Abstract Biomolecular condensates regulate cellular physiology by sequestering and processing RNAs and proteins, yet how these processes are locally tuned within condensates remains unclear. Moreover, in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), condensates undergo liquid-to-solid phase transitions, but capturing early intermediates in this process has been challenging. Here, we present a surface multi-tethering approach to achieve intra-condensate single-molecule tracking of fluorescently labeled RNA and protein molecules within liquid-like condensates. Using RNA-binding protein Fused in Sarcoma (FUS) as a model for condensates implicated in ALS, we discover that RNA and protein diffusion is confined within distinct nanometer-scale domains, or nanodomains, which exhibit unique connectivity and chemical environments. During condensate aging, these nanodomains reposition, facilitating FUS fibrilization at the condensate surface, a transition enhanced by FDA-approved ALS drugs. Our findings demonstrate that nanodomain formation governs condensate function by modulating biomolecule sequestration and percolation, offering insights into condensate aging and disease-related transitions. Biological sciences/Biotechnology/Nanobiotechnology/Nanoparticles Physical sciences/Nanoscience and technology/Nanoscale materials/Molecular self-assembly Full Text Additional Declarations There is NO Competing Interest. Supplementary Files NanodomainNatNanotech2025SupplInfoFinal.pdf Cite Share Download PDF Status: Published Journal Publication published 14 Nov, 2025 Read the published version in Nature Nanotechnology → 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-6406576","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":441773866,"identity":"ba8955ae-a35d-45c8-b99f-e3687e9ddadb","order_by":0,"name":"Nils Walter","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuUlEQVRIiWNgGAWjYHACxgNAQg5INzCDeA3E6DkA1GNMupZEkEritJhLJD84/KHiXvqGa4cbPxcw2MhuOEBAi+WMNIMDB84U5264ndgsPYMhzZigFoPbCQYHDrYlgLS0MfMwHE4kQkv6hwMH/yWkG0C0/CdGSw7QloaEBKiWA0Rouf+m4MCZYwmGM0F+4TFINp5JUMuZ4xsfVNQkyPPdTn/4mafCTraPkBZ0E0hTPgpGwSgYBaMABwAAX/JNY+3aE8oAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-7301-1275","institution":"University of Michigan","correspondingAuthor":true,"prefix":"","firstName":"Nils","middleName":"","lastName":"Walter","suffix":""},{"id":441773867,"identity":"c9620bd5-182b-4f2c-8005-7060ff0741d6","order_by":1,"name":"Guoming Gao","email":"","orcid":"https://orcid.org/0000-0001-6791-3902","institution":"California Institute of Technology","correspondingAuthor":false,"prefix":"","firstName":"Guoming","middleName":"","lastName":"Gao","suffix":""},{"id":441773868,"identity":"464cac99-740b-4c12-9047-10ccee41b9c4","order_by":2,"name":"Emily Sumrall","email":"","orcid":"https://orcid.org/0000-0001-7789-4119","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Emily","middleName":"","lastName":"Sumrall","suffix":""}],"badges":[],"createdAt":"2025-04-08 22:40:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6406576/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6406576/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41565-025-02077-x","type":"published","date":"2025-11-14T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":95972963,"identity":"8dddc455-0a22-4d7d-bffc-24f758774fe9","added_by":"auto","created_at":"2025-11-15 08:05:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2080304,"visible":true,"origin":"","legend":"","description":"","filename":"NanodomainNatNanotech2025MainFinal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6406576/v1_covered_7590f1ff-351c-453b-b20a-a642d308942d.pdf"},{"id":80502022,"identity":"5ee81f09-058a-4b24-a924-3d86e5d44ca0","added_by":"auto","created_at":"2025-04-14 03:47:48","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14552668,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"NanodomainNatNanotech2025SupplInfoFinal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6406576/v1/a64fba6c18954f7a8be7669b.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Nanoscale domains govern local diffusion and aging within FUS condensates","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6406576/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6406576/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Biomolecular condensates regulate cellular physiology by sequestering and processing RNAs and proteins, yet how these processes are locally tuned within condensates remains unclear. 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