Itaconate-based nanoparticles induce immunometabolic reprogramming in macrophages and alleviate diet-induced obesity

Itaconate-based nanoparticles induce immunometabolic reprogramming in macrophages and alleviate diet-induced obesity | 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 Itaconate-based nanoparticles induce immunometabolic reprogramming in macrophages and alleviate diet-induced obesity Ryan Pearson, Andrea Cottingham, Neda Mohaghegh, Sara Kolhatkar, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8604693/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Obesity is driven by chronic adipose tissue inflammation and macrophage dysfunction. Here, we report a cargo-free nanoparticle (NP) platform derived from itaconate-based polyesters (pITA-NPs) that reprograms macrophage immunometabolism and alleviates diet-induced obesity. pITA-NPs rapidly induce CD206 presentation through a translationally independent mechanism and drive a non-canonical M2-like transcriptional and metabolic state distinct from IL-4/STAT6 polarization, while restraining inflammatory activation and macrophage-adipocyte crosstalk to reduce lipid accumulation. Bioenergetic profiling revealed context-dependent metabolic tuning, with pITA-NPs promoting a non-canonical M2-like metabolic transition in resting macrophages characterized by increased mitochondrial mass and oxidative phosphorylation, while inducing a metabolically restrained, quiescent-like state in M1-like macrophages. In obese mice, subcutaneous pITA-NP treatment suppresses weight gain, reduces adiposity, promotes adipose tissue beiging and brown fat activation, and mitigates systemic inflammatory responses. Together, these findings establish pITA-NPs as an effective immunometabolic nanotherapy that leverages materials-driven macrophage reprogramming and coordinates immune and metabolic regulation to treat obesity. Physical sciences/Engineering/Biomedical engineering Biological sciences/Biotechnology/Nanobiotechnology/Nanoparticles Macrophage polarization Inflammation Obesity Metabolism Nanoparticle Adipose tissue Thermogenesis Mitochondria Full Text Additional Declarations Yes there is potential Competing Interest. R.M.P., A.H.N., and A.L.C are listed inventors on a patent filed by the University of Maryland, Baltimore and Terasaki Institute related to the use of metabolite-based polymers and nanoparticles for the treatment of inflammatory diseases. Supplementary Files SupplementalObesityManuscriptFINAL.pdf Supplementary Information Cite Share Download PDF Status: Posted 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-8604693","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":575036709,"identity":"38eb78b3-1807-43dd-8150-140833749dce","order_by":0,"name":"Ryan Pearson","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIiWNgGAWjYDADfjiLHYh5GBgYGwhpkYSrYCZWi8EBYrWYz24++Lnij02e8e0zBsy8OXb5BoeZnz14w2Aju+EAdi0yd44lS55tSys2O5eWwMy7Ldlyw2E2c8M5DGnGuLRISOQYSDY2HE7cdob5AFALs4HBYQYzaR6Gw4m4teR//tnw53Di5h7GBqCWeqAW9m9ALf/xaMlhk2xgA5rJA7blMFALD8iWA7i1yBwzs2xsS0uccYYt4eDcbccNJA/zlEnOMUg2nolLi3Tz45sNf2wS+3t4DB+83VZtwHe8fZvEmwo72T4cWhgkkNhgNQpg0gCHcnQtYCDfgEf1KBgFo2AUjEgAAPJhW1JiWVH9AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-7857-0973","institution":"University of Maryland, Baltimore","correspondingAuthor":true,"prefix":"","firstName":"Ryan","middleName":"","lastName":"Pearson","suffix":""},{"id":575036710,"identity":"a7f9ff74-811d-4c81-ab0f-1c2f883b5446","order_by":1,"name":"Andrea Cottingham","email":"","orcid":"https://orcid.org/0000-0001-9067-2537","institution":"University of Maryland, Baltimore","correspondingAuthor":false,"prefix":"","firstName":"Andrea","middleName":"","lastName":"Cottingham","suffix":""},{"id":575036711,"identity":"ae34c566-df60-48d2-a5cb-f3b24304fc11","order_by":2,"name":"Neda Mohaghegh","email":"","orcid":"","institution":"Terasaki Institute for Biomedical Innovation","correspondingAuthor":false,"prefix":"","firstName":"Neda","middleName":"","lastName":"Mohaghegh","suffix":""},{"id":575036712,"identity":"212bb65b-59d3-414d-ae15-0500ad7993aa","order_by":3,"name":"Sara Kolhatkar","email":"","orcid":"","institution":"University of Maryland, Baltimore","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Kolhatkar","suffix":""},{"id":575036713,"identity":"ecb604cd-6c07-4200-96d5-0fce659b362e","order_by":4,"name":"Fanny Xu","email":"","orcid":"","institution":"University of Maryland, Baltimore","correspondingAuthor":false,"prefix":"","firstName":"Fanny","middleName":"","lastName":"Xu","suffix":""},{"id":575036714,"identity":"8e400857-7fa0-475d-adc3-99d4cc9df6b1","order_by":5,"name":"Shruti Dharmaraj","email":"","orcid":"","institution":"University of Maryland, Baltimore","correspondingAuthor":false,"prefix":"","firstName":"Shruti","middleName":"","lastName":"Dharmaraj","suffix":""},{"id":575036715,"identity":"ffd7fc7a-a477-4b14-b06c-a82e88f56da0","order_by":6,"name":"Jacob Shaw","email":"","orcid":"","institution":"University of Maryland, Baltimore","correspondingAuthor":false,"prefix":"","firstName":"Jacob","middleName":"","lastName":"Shaw","suffix":""},{"id":575036716,"identity":"84331e65-1422-4872-b96f-95ba02416479","order_by":7,"name":"Sanmoy Pathak","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Sanmoy","middleName":"","lastName":"Pathak","suffix":""},{"id":575036717,"identity":"788d11df-65ae-4d40-89f6-b413ceefeb1b","order_by":8,"name":"Victor Andrade","email":"","orcid":"","institution":"University of Maryland, Batimore","correspondingAuthor":false,"prefix":"","firstName":"Victor","middleName":"","lastName":"Andrade","suffix":""},{"id":575036718,"identity":"326f3a9d-c41a-4549-8773-f89055d36d54","order_by":9,"name":"Yan Shu","email":"","orcid":"","institution":"University of Maryland, Batimore","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Shu","suffix":""},{"id":575036719,"identity":"79073e33-8778-40ba-adde-a4721158f626","order_by":10,"name":"Abhinav Acharya","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Abhinav","middleName":"","lastName":"Acharya","suffix":""},{"id":575036720,"identity":"3845213f-975d-4557-9af4-eda8b6d69881","order_by":11,"name":"Alireza Najafabadi","email":"","orcid":"","institution":"University of Cincinnati","correspondingAuthor":false,"prefix":"","firstName":"Alireza","middleName":"","lastName":"Najafabadi","suffix":""}],"badges":[],"createdAt":"2026-01-14 19:25:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8604693/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8604693/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102745410,"identity":"0cc5749e-c1bf-48a5-ba1e-9ad67e40421c","added_by":"auto","created_at":"2026-02-16 08:49:13","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5479521,"visible":true,"origin":"","legend":"Article File","description":"","filename":"ObesityManuscriptFINAL.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8604693/v1_covered_91a23bc4-1611-4467-8957-f8fb66b679c5.pdf"},{"id":101304175,"identity":"f1fb597d-71dd-4082-b705-bdec02e8d70b","added_by":"auto","created_at":"2026-01-28 10:01:46","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":8828093,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"SupplementalObesityManuscriptFINAL.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8604693/v1/7c8abaf36527430a325f195c.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nR.M.P., A.H.N., and A.L.C are listed inventors on a patent filed by the University of Maryland, Baltimore and Terasaki Institute related to the use of metabolite-based polymers and nanoparticles for the treatment of inflammatory diseases.","formattedTitle":"Itaconate-based nanoparticles induce immunometabolic reprogramming in macrophages and alleviate diet-induced obesity","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Macrophage polarization, Inflammation, Obesity, Metabolism, Nanoparticle, Adipose tissue, Thermogenesis, Mitochondria","lastPublishedDoi":"10.21203/rs.3.rs-8604693/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8604693/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Obesity is driven by chronic adipose tissue inflammation and macrophage dysfunction. Here, we report a cargo-free nanoparticle (NP) platform derived from itaconate-based polyesters (pITA-NPs) that reprograms macrophage immunometabolism and alleviates diet-induced obesity. pITA-NPs rapidly induce CD206 presentation through a translationally independent mechanism and drive a non-canonical M2-like transcriptional and metabolic state distinct from IL-4/STAT6 polarization, while restraining inflammatory activation and macrophage-adipocyte crosstalk to reduce lipid accumulation. Bioenergetic profiling revealed context-dependent metabolic tuning, with pITA-NPs promoting a non-canonical M2-like metabolic transition in resting macrophages characterized by increased mitochondrial mass and oxidative phosphorylation, while inducing a metabolically restrained, quiescent-like state in M1-like macrophages. In obese mice, subcutaneous pITA-NP treatment suppresses weight gain, reduces adiposity, promotes adipose tissue beiging and brown fat activation, and mitigates systemic inflammatory responses. Together, these findings establish pITA-NPs as an effective immunometabolic nanotherapy that leverages materials-driven macrophage reprogramming and coordinates immune and metabolic regulation to treat obesity.","manuscriptTitle":"Itaconate-based nanoparticles induce immunometabolic reprogramming in macrophages and alleviate diet-induced obesity","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-28 09:54:43","doi":"10.21203/rs.3.rs-8604693/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"63055411-79dd-4a3f-9410-9e4d25b8483f","owner":[],"postedDate":"January 28th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":61186714,"name":"Physical sciences/Engineering/Biomedical engineering"},{"id":61186715,"name":"Biological sciences/Biotechnology/Nanobiotechnology/Nanoparticles"}],"tags":[],"updatedAt":"2026-02-11T17:16:30+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-28 09:54:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8604693","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8604693","identity":"rs-8604693","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}