Controlled production of bacterial outer membrane vesicles in intestine by orally administered bacteria as an effective tumor vaccine

Controlled production of bacterial outer membrane vesicles in intestine by orally administered bacteria as an effective tumor vaccine | 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 Controlled production of bacterial outer membrane vesicles in intestine by orally administered bacteria as an effective tumor vaccine Yale Yue, Jiaqi Xu, Yao Li, Keman Cheng, Qingqing Feng, Xiaotu Ma, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-690237/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 May, 2022 Read the published version in Nature Biomedical Engineering → Version 1 posted You are reading this latest preprint version Abstract Therapeutic tumor vaccines hold great promise for effective tumor immunotherapy, however orally administered tumor vaccines that can stimulate a robust immune response are still limited. The major challenges in oral vaccines are the complex gastrointestinal environment and intestinal epithelial barriers. Numerous intestinal commensal bacteria interact with the host immune cells through the release of outer membrane vesicles (OMVs) which can penetrate the intestinal epithelial barriers. Here, we present an effective tumor vaccine based on the OMVs which are generated by orally administered genetically engineered bacteria in intestine. A tumor antigen was fused with the surface protein ClyA on OMVs, whose expression was controlled by an arabinose-inducible promoter. Through oral administration of the modified bacteria and arabinose, in situ controllable production of OMVs loaded with tumor antigen in the intestine was achieved. The OMV-based tumor vaccine not only overcame the intestinal epithelial barriers to reach the immune cells in the lamina propria, but also stimulated dendritic cell maturation to facilitate a potent antitumor adaptive immunity. The oral bacteria generated OMV-based tumor vaccine significantly inhibited the lung metastatic melanoma and subcutaneous colon cancer in mouse models. Furthermore, a robust immune memory was generated, offering long-term protection against tumor challenge. Our work provides a proof-of-concept for oral bacteria generated OMV-based tumor vaccine that may be further developed and translated into clinical use. Cancer Biology Immunology Vaccine Development Gastrointestinal Environment Intestinal Epithelial Barriers Intestinal Commensal Bacteria Arabinose-inducible Promoter Dendritic Cell Maturation Full Text Additional Declarations Yes there is potential Competing Interest. G.N., X.Z., Y.L. are inventors on a filed provisional application China patent (Oral vaccine system based on membrane vesicle strategy) submitted by the National Center for Nanoscience and Technology that covers the potential diagnostic and therapeutic uses of the oral vaccine for cancer immunotherapy. The authors declare that they have no other competing interests. Cite Share Download PDF Status: Published Journal Publication published 02 May, 2022 Read the published version in Nature Biomedical Engineering → 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-690237","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":39097651,"identity":"ad8055a6-749b-4e48-81a9-2c196550495e","order_by":0,"name":"Yale Yue","email":"","orcid":"","institution":"National Center for Nanoscience and Technology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yale","middleName":"","lastName":"Yue","suffix":""},{"id":39097652,"identity":"0b8c9da0-87e9-4bad-8a81-48319b932fcf","order_by":1,"name":"Jiaqi Xu","email":"","orcid":"","institution":"National Center for Nanoscience and 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diagnostic and therapeutic uses of the oral vaccine for cancer immunotherapy. The authors declare that they have no other competing interests.","formattedTitle":"Controlled production of bacterial outer membrane vesicles in intestine by orally administered bacteria as an effective tumor vaccine","fulltext":[{"header":"Full Text","content":"This preprint is available for \u003ca href='/article/rs-690237/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e."}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":false,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"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":"Gastrointestinal Environment, Intestinal Epithelial Barriers, Intestinal Commensal Bacteria, Arabinose-inducible Promoter, Dendritic Cell Maturation","lastPublishedDoi":"10.21203/rs.3.rs-690237/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-690237/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTherapeutic tumor vaccines hold great promise for effective tumor immunotherapy, however orally administered tumor vaccines that can stimulate a robust immune response are still limited. The major challenges in oral vaccines are the complex gastrointestinal environment and intestinal epithelial barriers. Numerous intestinal commensal bacteria interact with the host immune cells through the release of outer membrane vesicles (OMVs) which can penetrate the intestinal epithelial barriers. Here, we present an effective tumor vaccine based on the OMVs which are generated by orally administered genetically engineered bacteria in intestine. A tumor antigen was fused with the surface protein ClyA on OMVs, whose expression was controlled by an arabinose-inducible promoter. Through oral administration of the modified bacteria and arabinose, \u003cem\u003ein situ\u003c/em\u003e controllable production of OMVs loaded with tumor antigen in the intestine was achieved. The OMV-based tumor vaccine not only overcame the intestinal epithelial barriers to reach the immune cells in the lamina propria, but also stimulated dendritic cell maturation to facilitate a potent antitumor adaptive immunity. The oral bacteria generated OMV-based tumor vaccine significantly inhibited the lung metastatic melanoma and subcutaneous colon cancer in mouse models. Furthermore, a robust immune memory was generated, offering long-term protection against tumor challenge. Our work provides a proof-of-concept for oral bacteria generated OMV-based tumor vaccine that may be further developed and translated into clinical use.\u003c/p\u003e","manuscriptTitle":"Controlled production of bacterial outer membrane vesicles in intestine by orally administered bacteria as an effective tumor vaccine","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-07-14 18:59:21","doi":"10.21203/rs.3.rs-690237/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-biomedical-engineering","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"natbiomedeng","sideBox":"Learn more about [Nature Biomedical Engineering](http://www.nature.com/natbiomedeng/)","snPcode":"41551","submissionUrl":"https://mts-natbiomedeng.nature.com/cgi-bin/main.plex","title":"Nature Biomedical Engineering","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"8976d7b3-e263-49ac-95a5-e92cdc960390","owner":[],"postedDate":"July 14th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":5717629,"name":"Cancer Biology"},{"id":5717630,"name":"Immunology"},{"id":5717631,"name":"Vaccine Development"}],"tags":[],"updatedAt":"2022-05-03T07:11:39+00:00","versionOfRecord":{"articleIdentity":"rs-690237","link":"https://doi.org/10.1038/s41551-022-00886-2","journal":{"identity":"nature-biomedical-engineering","isVorOnly":false,"title":"Nature Biomedical Engineering"},"publishedOn":"2022-05-02 04:00:00","publishedOnDateReadable":"May 2nd, 2022"},"versionCreatedAt":"2021-07-14 18:59:21","video":"","vorDoi":"10.1038/s41551-022-00886-2","vorDoiUrl":"https://doi.org/10.1038/s41551-022-00886-2","workflowStages":[]},"version":"v1","identity":"rs-690237","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-690237","identity":"rs-690237","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}