Niosomal In Situ Gel Enhances the Ocular Bioavailability of Kaempferol and Improves Therapeutic Efficacy in Dry Eye Disease

Niosomal In Situ Gel Enhances the Ocular Bioavailability of Kaempferol and Improves Therapeutic Efficacy in Dry Eye Disease | 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 Niosomal In Situ Gel Enhances the Ocular Bioavailability of Kaempferol and Improves Therapeutic Efficacy in Dry Eye Disease Xue He, Zheng Liu, Xiaping Yao, Zhen Liang, Tao Wu, Yinjian Ji, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9191012/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 14 You are reading this latest preprint version Abstract Background Conventional dry eye formulations frequently demonstrate low bioavailability and necessitate high dosing frequency, resulting in poor patient compliance. This is largely due to the ocular physiological barrier. Aim of the study We developed a novel ophthalmic formulation, kaempferol-loaded niosomal in situ gel (KAE-NIO-ISG), to improve the treatment of dry eye disease by increasing the ocular bioavailability and therapeutic efficacy. Materials and methods KAE-NIO-ISG was prepared by thin-film hydration and incorporated into an ion-sensitive in situ gel. Results The optimized KAE-NIO-ISG exhibited nanoscale characteristics particle size (PS) 177.27± 1.26 nm; polydispersity index (PDI) 0.21±0.03. The viscosity increased markedly upon dilution with simulated tear fluid (from 27.24±0.49 cP to 238.71±1.75 cP), indicating effective in situ gelation. Approximately 60% of the kaempferol（KAE） was released after 72 h, which is substantially greater than that of the KAE suspension (16.62±5.74%). The formulation demonstrated robust storage stability, no cytotoxicity in Human corneal epithelial cells (HCE-2) or Rat conjunctival epithelial cells (rPCEC), and excellent ocular tolerance. Pharmacokinetic analysis revealed that compared with the KAE suspension, KAE-NIO-ISG increased AUC 0-180 min values in the rabbit cornea and conjunctiva by 23.52-fold and 3.98-fold, respectively. In vivo pharmacodynamics revealed dose-dependent efficacy, with the high-dose group achieving effects comparable to those of cyclosporine A (CsA). Conclusions In summary, KAE-NIO-ISG is a well-tolerated, efficient therapeutic approach for dry eye disease that significantly enhances ocular bioavailability and therapeutic outcomes. Health sciences/Diseases Biological sciences/Drug discovery Health sciences/Medical research Dry eye disease Kaempferol Niosome In situ gel Ocular drug delivery Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 20 Apr, 2026 Reviews received at journal 16 Apr, 2026 Reviews received at journal 14 Apr, 2026 Reviews received at journal 10 Apr, 2026 Reviews received at journal 04 Apr, 2026 Reviewers agreed at journal 01 Apr, 2026 Reviewers agreed at journal 27 Mar, 2026 Reviewers agreed at journal 27 Mar, 2026 Reviewers agreed at journal 27 Mar, 2026 Reviewers invited by journal 26 Mar, 2026 Editor assigned by journal 26 Mar, 2026 Editor invited by journal 26 Mar, 2026 Submission checks completed at journal 25 Mar, 2026 First submitted to journal 25 Mar, 2026 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-9191012","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":613960228,"identity":"b50ce86d-d27a-42c6-a96b-05649bd1844e","order_by":0,"name":"Xue He","email":"","orcid":"","institution":"Henan University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xue","middleName":"","lastName":"He","suffix":""},{"id":613960229,"identity":"feb0f237-5415-4b97-b03f-5d5b05af0ca8","order_by":1,"name":"Zheng Liu","email":"","orcid":"","institution":"First Affiliated Hospital of Zhengzhou 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University of Traditional Chinese Medicine","correspondingAuthor":true,"prefix":"","firstName":"Yuwei","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2026-03-22 12:08:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9191012/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9191012/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106401282,"identity":"8dc73a8d-1928-45af-8558-72f7b6812ba9","added_by":"auto","created_at":"2026-04-08 08:45:28","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1837061,"visible":true,"origin":"","legend":"","description":"","filename":"NiosomalInSituGelEnhancestheOcularBioavaila.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9191012/v1_covered_24031fd0-36ec-4c0f-91a4-45438225c438.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Niosomal In Situ Gel Enhances the Ocular Bioavailability of Kaempferol and Improves Therapeutic Efficacy in Dry Eye Disease","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Dry eye disease, Kaempferol, Niosome, In situ gel, Ocular drug delivery","lastPublishedDoi":"10.21203/rs.3.rs-9191012/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9191012/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConventional dry eye formulations frequently demonstrate low bioavailability and necessitate high dosing frequency, resulting in poor patient compliance. This is largely due to the ocular physiological barrier.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim of the study\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe developed a novel ophthalmic formulation, kaempferol-loaded niosomal in situ gel (KAE-NIO-ISG), to improve the treatment of dry eye disease by increasing the ocular bioavailability and therapeutic efficacy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and methods\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eKAE-NIO-ISG was prepared by thin-film hydration and incorporated into an ion-sensitive in situ gel.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eThe optimized KAE-NIO-ISG exhibited nanoscale characteristics particle size (PS) 177.27± 1.26 nm; polydispersity index (PDI) 0.21±0.03. The viscosity increased markedly upon dilution with simulated tear fluid (from 27.24±0.49 cP to 238.71±1.75 cP), indicating effective in situ gelation. Approximately 60% of the kaempferol（KAE） was released after 72 h, which is substantially greater than that of the KAE suspension (16.62±5.74%). The formulation demonstrated robust storage stability, no cytotoxicity in Human corneal epithelial cells (HCE-2) or Rat conjunctival epithelial cells (rPCEC), and excellent ocular tolerance. Pharmacokinetic analysis revealed that compared with the KAE suspension, KAE-NIO-ISG increased \u0026nbsp;AUC\u003csub\u003e0-180 min\u003c/sub\u003e values in the rabbit cornea and conjunctiva by 23.52-fold and 3.98-fold, respectively. In vivo pharmacodynamics revealed dose-dependent efficacy, with the high-dose group achieving effects comparable to those of cyclosporine A (CsA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn summary, KAE-NIO-ISG is a well-tolerated, efficient therapeutic approach for dry eye disease that significantly enhances ocular bioavailability and therapeutic outcomes.\u003c/p\u003e","manuscriptTitle":"Niosomal In Situ Gel Enhances the Ocular Bioavailability of Kaempferol and Improves Therapeutic Efficacy in Dry Eye Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-30 15:32:52","doi":"10.21203/rs.3.rs-9191012/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-20T15:28:19+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-16T06:33:56+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-14T11:14:49+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-10T14:50:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-04T04:02:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"88147094166143424774024224470489950797","date":"2026-04-01T04:48:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"223037011729898240611373379798692576980","date":"2026-03-27T10:47:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"5850566988460323328725089977714808845","date":"2026-03-27T05:10:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"265905613820989558434205984288452459246","date":"2026-03-27T04:57:11+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-27T03:59:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-27T03:18:30+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-27T01:06:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-25T17:54:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-03-25T16:09:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"67fb92d1-f42b-4c15-822a-df58dae95516","owner":[],"postedDate":"March 30th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":65330742,"name":"Health sciences/Diseases"},{"id":65330743,"name":"Biological sciences/Drug discovery"},{"id":65330744,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2026-05-06T12:53:59+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-30 15:32:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9191012","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9191012","identity":"rs-9191012","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}