{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:26Z","timestamp":1787028566697,"version":"build-2736575974"},"reference-count":83,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T00:00:00Z","timestamp":1752624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universiti Kebangsaan Malaysia","award":["FF-2022-065\/1"],"award-info":[{"award-number":["FF-2022-065\/1"]}]},{"name":"Universiti Kebangsaan Malaysia","award":["DPK-2023-004"],"award-info":[{"award-number":["DPK-2023-004"]}]},{"name":"Universiti Kebangsaan Malaysia","award":["GP-K020811"],"award-info":[{"award-number":["GP-K020811"]}]},{"name":"Universiti Kebangsaan Malaysia","award":["TAP-K020811"],"award-info":[{"award-number":["TAP-K020811"]}]},{"name":"Universiti Kebangsaan Malaysia","award":["FF-2022-065"],"award-info":[{"award-number":["FF-2022-065"]}]},{"name":"Medixcell Sdn. Bhd.","award":["FF-2022-065\/1"],"award-info":[{"award-number":["FF-2022-065\/1"]}]},{"name":"Medixcell Sdn. Bhd.","award":["DPK-2023-004"],"award-info":[{"award-number":["DPK-2023-004"]}]},{"name":"Medixcell Sdn. Bhd.","award":["GP-K020811"],"award-info":[{"award-number":["GP-K020811"]}]},{"name":"Medixcell Sdn. Bhd.","award":["TAP-K020811"],"award-info":[{"award-number":["TAP-K020811"]}]},{"name":"Medixcell Sdn. Bhd.","award":["FF-2022-065"],"award-info":[{"award-number":["FF-2022-065"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Umbilical cord mesenchymal stem cells (UCMSCs)-derived small extracellular vehicles (sEVs) are reported to offer therapeutic effects in regenerative medicine, but they lack safety and biodistribution profiles to support smooth translation at the clinical stage and regulatory requirements. Our study aimed to determine the safety and biodistribution profile in a healthy animal model before application in the metabolic syndrome model. Method: Healthy male Sprague Dawley (SD) rats were given an intravenous (IV) injection of normal saline (control group) or pooled fetal UCMSCs-derived sEVs (treated group) every three weeks for 90 days. Morbidity and mortality observation (daily), physical measurements (weekly), selected serum biochemistry (every three weeks), and hematology (every three weeks) were performed for 90 days. Acute toxicity (on day 14) and sub-chronic toxicity (on day 90) were assessed for gross necropsy, relative organ weight, and histopathological assessment of lungs, liver, spleen, kidney, and lymph nodes. Separately, a biodistribution study was conducted with the sEVs preparations labeled with PKH26 fluorescent dye, given intravenously to the rats. The organs were harvested 24 h post-injection. There were no drastic changes in either group\u2019s morbidity or mortality, physical, hematological, and biochemistry evaluation. The histopathological assessment concluded moderate (focal) inflammation in the treated group\u2019s kidneys and signs of recovery from the inflammation and vascular congestion in the liver. A biodistribution study revealed a higher accumulation of sEVs in the spleen. Multiple IV injections of the pooled fetal UCMSCs-derived sEVs in healthy male SD rats were deemed safe. The sEVs were abundantly distributed in the spleen 24 h post-injection.<\/jats:p>","DOI":"10.3390\/ijms26146806","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T10:46:05Z","timestamp":1752662765000},"page":"6806","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Safety Evaluation and Biodistribution of Fetal Umbilical Cord Mesenchymal Stem Cells-Derived Small Extracellular Vesicles in Sprague Dawley Rats"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4916-2661","authenticated-orcid":false,"given":"Illayaraja","family":"Krishnan","sequence":"first","affiliation":[{"name":"Department of Tissue Engineering and Regenerative Medicine (DTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Cheras, Kuala Lumpur 56000, Malaysia"},{"name":"National Pharmaceutical Regulatory Agency (NPRA), Lot 36, Jalan Prof Diraja Ungku Aziz, Petaling Jaya 46200, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5394-7068","authenticated-orcid":false,"given":"Ubashini","family":"Vijakumaran","sequence":"additional","affiliation":[{"name":"Department of Tissue Engineering and Regenerative Medicine (DTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Cheras, Kuala Lumpur 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ng Min","family":"Hwei","sequence":"additional","affiliation":[{"name":"Department of Tissue Engineering and Regenerative Medicine (DTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Cheras, Kuala Lumpur 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9045-5145","authenticated-orcid":false,"given":"Law Jia","family":"Xian","sequence":"additional","affiliation":[{"name":"Department of Tissue Engineering and Regenerative Medicine (DTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Cheras, Kuala Lumpur 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohd Rafizul","family":"Mohd Yusof","sequence":"additional","affiliation":[{"name":"Department of Parasitology and Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thavachelvi","family":"Thangarajah","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Hospital Angkatan Tentera (HAT) Tuanku Mizan, Kuala Lumpur 53300, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2289-7619","authenticated-orcid":false,"given":"Tan Geok","family":"Chin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4897-9927","authenticated-orcid":false,"given":"Yin Ping","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anusha","family":"Kalyanasundaram","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hospital Raja Permaisuri Bainun (HRPB), Ipoh 30450, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zalina","family":"Mahmood","sequence":"additional","affiliation":[{"name":"Production and Blood Supply Management Division, National Blood Centre, Kuala Lumpur 50400, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shathiya","family":"Rajamanickam","sequence":"additional","affiliation":[{"name":"Medixcell Sdn. 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