{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T09:13:59Z","timestamp":1775207639189,"version":"3.50.1"},"reference-count":57,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000},"content-version":"vor","delay-in-days":92,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Stem Cells International"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Due to toxicity, high costs, and potential side effects of standard treatments of rheumatoid arthritis (RA) including nonsteroidal anti\u2010inflammatory drugs (NSAIDs), corticosteroids, and disease\u2010modifying antirheumatic drugs (DMARDs), natural products and advanced drug delivery systems, such as nanoparticles and mesenchymal stem cell (MSC)\u2013derived exosomes (EXO), have garnered interest due to their ability to target inflammation and oxidative damage, with enhanced precision and reduced side effects, offering a promising approach for RA management.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>EXO were isolated from the conditioned medium of bone marrow\u2013derived MSCs (BM\u2010MSCs). Rutin (RT)\u2010loaded chitosan (Cs)\/pectin nanoparticles were prepared using a modified ionic gelation technique to enhance stability and bioavailability. Sixty male Wistar rats were utilized in the in vivo experiment and randomly assigned to six groups, each comprising 10 animals. These groups were (1) normal control, (2) complete Freund\u2019s adjuvant (CFA)\u2010induced arthritic control, (3) CFA\u2010induced arthritis treated with free RT (20\u2009mg\/kg), (4) CFA\u2010induced arthritis treated with EXO (100\u2009\u00b5g protein per rat, intravenous injection, once weekly), (5) CFA\u2010induced arthritis treated with RT\u2010Cs\u2013pectin nanocomposite (RT\u2010CPN) (20\u2009mg\/kg), and (6) CFA\u2010induced arthritis treated with a combination of RT\u2010CPN and EXO. Treatments were administered for 28 days, after which the rats were euthanized for further analysis. For molecular evaluations, blood was collected for serum isolation, and the right ankle joint was carefully dissected.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Treatment with RT, EXO, RT\u2010CPN, and especially, EXO\u2009+\u2009RT\u2010CPN combination significantly reduced serum levels of anticitrullinated protein antibodies (ACPAs), interleukin\u20101\u03b2 (IL\u20101\u03b2), interleukin\u20106 (IL\u20106), and the marker of oxidative stress malondialdehyde (MDA). These treatments also decreased inducible nitric oxide synthase (iNOS) mRNA expression, a key regulator of oxidative and inflammatory processes. Conversely, antioxidant defenses improved, as indicated by increased serum glutathione (GSH), interleukin\u201010 (IL\u201010), and interleukin\u201013 (IL\u201013) levels, along with upregulation of antioxidant enzymes such glutathione peroxidase (GPx), glutathione S\u2010transferase (GST), glutathione reductase (GR), and superoxide dismutase (SOD). Joint degradation was notably reduced by suppressing the protein levels of MMP\u20101, MMP\u20103, MMP\u20109, and MMP\u201013, while nuclear factor erythroid 2\u2013related factor 2 (Nrf2) expression, a critical regulator of cellular protection, was elevated. Along with improvements in functional and molecular markers, the right hind leg\u2019s swelling and redness decreased, and the histological alterations including pannus development, inflammatory cell infiltrations, synovial membrane hyperplasia, and degradation of articular cartilage were substantially suppressed after treatments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The combination of EXO + RT\u2010CPN demonstrated the strongest antiarthritic effects, reducing inflammation, oxidative stress, and joint degradation while boosting the body\u2019s antioxidant defenses. These findings highlight a promising, safer therapeutic strategy for RA management.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/sci\/3586025","type":"journal-article","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T08:16:36Z","timestamp":1775204196000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MSC Exosomes and Rutin\u2010Chitosan\u2013Pectin Nanoparticles Synergize to Ameliorate Adjuvant Arthritis via Th1\/Th2 Modulation, MMP Suppression, Nrf2 Upregulation, and Antioxidant Boost"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5098-1513","authenticated-orcid":false,"given":"Karim M.","family":"Moftah","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1981-8382","authenticated-orcid":false,"given":"Walaa G.","family":"Hozayen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1034-0458","authenticated-orcid":false,"given":"Nabil A.","family":"Hasona","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5054-4610","authenticated-orcid":false,"given":"Hessah M.","family":"Al-Muzafar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2487-8427","authenticated-orcid":false,"given":"Kamal A.","family":"Amin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0160-9857","authenticated-orcid":false,"given":"Hussah A.","family":"Alshwyeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0896-4499","authenticated-orcid":false,"given":"Khairy M. A.","family":"Zoheir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3781-9709","authenticated-orcid":false,"given":"Osama M.","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,3]]},"reference":[{"key":"e_1_2_14_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2019.102400"},{"key":"e_1_2_14_2_2","article-title":"Hesperidin Suppresses Complete Freund\u2019s Adjuvant (Cfa)-Induced Rheumatoid Arthritis (Ra) in Rats by Blocking Tnf-\/Il-6\/Il-1 and Nf-Kb\/Cox-2 Signaling","volume":"4","author":"Aja P. M.","year":"2013","journal-title":"Social Science Research Network"},{"key":"e_1_2_14_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2021.153766"},{"key":"e_1_2_14_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.berh.2025.102036"},{"key":"e_1_2_14_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(23)00211-4"},{"key":"e_1_2_14_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1004965"},{"key":"e_1_2_14_7_2","first-page":"1","article-title":"Immunomodulatory Roles of Metalloproteinases in Rheumatoid Arthritis","volume":"4","author":"Bian Y.","year":"2023","journal-title":"Frontiers in Pharmacology"},{"key":"e_1_2_14_8_2","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/7536805"},{"key":"e_1_2_14_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11091721"},{"key":"e_1_2_14_10_2","first-page":"1","article-title":"Rutin Attenuates Complete Inflammatory Pain in Rats Freund \u2019 s Adjuvant-Induced","volume":"8","author":"Forouzanfar F.","year":"2025","journal-title":"Iranian Journal of Basic Medical Sciences"},{"key":"e_1_2_14_11_2","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10111696"},{"key":"e_1_2_14_12_2","doi-asserted-by":"publisher","DOI":"10.1159\/000451027"},{"key":"e_1_2_14_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-023-02902-x"},{"key":"e_1_2_14_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tifs.2017.07.008"},{"key":"e_1_2_14_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2020.104468"},{"key":"e_1_2_14_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jddst.2020.102044"},{"key":"e_1_2_14_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2020.09.102"},{"key":"e_1_2_14_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ntm.2024.100040"},{"key":"e_1_2_14_19_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/polym17111453","article-title":"Chitosan Nanoparticle-Based Drug Delivery Systems: Advances, Challenges, and Future Perspectives","volume":"17","author":"Stefanache A.","year":"2025","journal-title":"Polymers"},{"key":"e_1_2_14_20_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules29235766"},{"key":"e_1_2_14_21_2","article-title":"Exosomes as Rheumatoid Arthritis Diagnostic Biomarkers and Therapeutic Agents","volume":"11","author":"Heydari R.","journal-title":"Vaccines"},{"key":"e_1_2_14_22_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-025-10290-z"},{"key":"e_1_2_14_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcma.2017.03.013"},{"key":"e_1_2_14_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1743-6109.2006.00153.x"},{"key":"e_1_2_14_25_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.9b01004"},{"key":"e_1_2_14_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2019.10.010"},{"key":"e_1_2_14_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2019.11.031"},{"key":"e_1_2_14_28_2","doi-asserted-by":"publisher","DOI":"10.1098\/rsos.210784"},{"key":"e_1_2_14_29_2","doi-asserted-by":"publisher","DOI":"10.4103\/0974-8490.75462"},{"key":"e_1_2_14_30_2","doi-asserted-by":"publisher","DOI":"10.1177\/1545968320926164"},{"key":"e_1_2_14_31_2","volume-title":"Theory and Practice of Histological Techniques","author":"Bancroft J.","year":"2002"},{"key":"e_1_2_14_32_2","doi-asserted-by":"publisher","DOI":"10.2174\/011574888X391650251119070246"},{"key":"e_1_2_14_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-24129-x"},{"key":"e_1_2_14_34_2","article-title":"Evaluation of Protective Efficacy of Avicennia marina (Forssk.) Vierh Leaves Against Complete Freund \u0313 s Adjuvant-Induced Arthritis in Wistar","volume":"13","author":"Gandomani M. Z.","year":"2014","journal-title":"Iranian Journal of Pharmaceutical Research"},{"key":"e_1_2_14_35_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-021-02105-2"},{"key":"e_1_2_14_36_2","doi-asserted-by":"crossref","first-page":"390","DOI":"10.5114\/ceji.2017.72807","article-title":"The Role of Anti-Citrullinated Protein Antibodies (ACPA) in the Pathogenesis of Rheumatoid Arthritis","volume":"42","author":"Kurowska W.","year":"2017","journal-title":"Central European Journal of Immunology"},{"key":"e_1_2_14_37_2","doi-asserted-by":"publisher","DOI":"10.1155\/2023\/2738351"},{"key":"e_1_2_14_38_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200103223441207"},{"key":"e_1_2_14_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.38328"},{"key":"e_1_2_14_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2016.07.015"},{"key":"e_1_2_14_41_2","doi-asserted-by":"crossref","DOI":"10.1007\/s11010-020-03948-8","article-title":"Protective Effect of Corynoline on the CFA Induced Rheumatoid Arthritis via Attenuation of Oxidative and Inflammatory Mediators","volume":"476","author":"Weng W.","year":"2021","journal-title":"Molecular and Cellular Biochemistry"},{"key":"e_1_2_14_42_2","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/2710607"},{"key":"e_1_2_14_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2019.02.006"},{"key":"e_1_2_14_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2021.107823"},{"key":"e_1_2_14_45_2","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S325988"},{"key":"e_1_2_14_46_2","article-title":"Transcriptional Regulation of Collagenase (MMP-1, MMP-13) Genes in Arthritis: Integration of Complex Signaling Pathways for the Recruitment of Gene-Specific Transcription Factors","volume":"3","author":"Vincenti M. P.","year":"2002","journal-title":"Arthritis Care & Research"},{"key":"e_1_2_14_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203239"},{"key":"e_1_2_14_48_2","doi-asserted-by":"publisher","DOI":"10.1177\/09603271211003311"},{"key":"e_1_2_14_49_2","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/8899143"},{"key":"e_1_2_14_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2021.174044"},{"key":"e_1_2_14_51_2","first-page":"1","article-title":"BM-MSC-Derived Exosomes Alleviate Radiation-Induced Bone Loss by Restoring the Function of Recipient BM-MSCs and Activating Wnt \/ \u03b2 -Catenin Signaling","volume":"3","author":"Zuo R.","year":"2019","journal-title":"Stem Cell Research & Therapy"},{"key":"e_1_2_14_52_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-011112-140320"},{"key":"e_1_2_14_53_2","first-page":"1","article-title":"An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation","volume":"8","author":"Saha S.","year":"2020","journal-title":"Molecules"},{"key":"e_1_2_14_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2021.119349"},{"key":"e_1_2_14_55_2","doi-asserted-by":"publisher","DOI":"10.1002\/biof.1599"},{"key":"e_1_2_14_56_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.33872"},{"key":"e_1_2_14_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2021.01.023"}],"container-title":["Stem Cells International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/sci\/3586025","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1155\/sci\/3586025","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/sci\/3586025","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T08:16:40Z","timestamp":1775204200000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1155\/sci\/3586025"}},"subtitle":[],"editor":[{"given":"Hussein M.","family":"El-Husseiny","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":57,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1155\/sci\/3586025"],"URL":"https:\/\/doi.org\/10.1155\/sci\/3586025","archive":["Portico"],"relation":{},"ISSN":["1687-966X","1687-9678"],"issn-type":[{"value":"1687-966X","type":"print"},{"value":"1687-9678","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"2025-07-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"3586025"}}