{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:21:16Z","timestamp":1791498076522,"version":"4.3.4"},"reference-count":23,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kentucky Pediatric Cancer Research Trust","award":["PON2 728 2000002500"],"award-info":[{"award-number":["PON2 728 2000002500"]}]},{"name":"MIB Agents Osteosarcoma Alliance"},{"name":"Biospecimen Procurement and Translational Pathology Shared Resource Facility of the University of Kentucky Markey Cancer Center","award":["P30CA177558"],"award-info":[{"award-number":["P30CA177558"]}]},{"name":"National Institute of General Medical Science KY INBRE network","award":["P20GM103436"],"award-info":[{"award-number":["P20GM103436"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Osteosarcoma (OS) is a relatively rare bone malignancy that primarily affects children and young adults and is associated with significant morbidity and mortality. Cisplatin is a mainstay of treatment, but its efficacy is limited by off-target toxicities. Immunotherapy is not effective due to a poor antigenic tumor microenvironment. Here, we address these challenges by using manufactured M1 macrophage-derived vesicles (MVs) loaded with cisplatin. Human blood and mouse RAW 264.7 M1 macrophages were used to prepare empty (E-MVs) and cisplatin-loaded MVs (C-MVs). Human OS cell lines were used in vitro and in a tibia xenograft mouse model to evaluate the anti-cancer and immune-stimulating abilities of MVs. C-MVs had lower IC50s but equivalent DNA damage in OS cell lines when compared with free cisplatin. E-MVs and C-MVs were observed to accumulate in the tumor in OS tumor-bearing mice. C-MVs significantly reduced tumor burden and prolonged survival in a mouse model of OS. Animals dosed with free cisplatin experienced weight loss and renal and hepatic toxicity, while equivalent doses of C-MVs did not cause these effects. In addition, both E-MVs and C-MVs showed immunomodulation of the tumor microenvironment with a significant increase in the M1\/M2 macrophages ratio (7-fold and 22-fold, respectively) and increased levels of TNF-\u03b1 in serum (1.8-fold and 2.1-fold, respectively) compared to control mice. Collectively, these experiments support further development of C-MVs for the treatment of OS.<\/jats:p>","DOI":"10.3390\/cells14201616","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T10:28:36Z","timestamp":1760696916000},"page":"1616","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Cisplatin-Loaded M1 Macrophage-Derived Vesicles Have Anti-Cancer Activity in Osteosarcoma"],"prefix":"10.3390","volume":"14","author":[{"given":"Namrata","family":"Anand","sequence":"first","affiliation":[{"name":"Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40536, USA"},{"name":"Department of Pharmacy Practice and Research, College of Pharmacy, University of Kentucky, Lexington, KY 40508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5028-8853","authenticated-orcid":false,"given":"Joseph Robert","family":"McCorkle","sequence":"additional","affiliation":[{"name":"Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Schweer","sequence":"additional","affiliation":[{"name":"Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40536, USA"},{"name":"Department of Obstetrics & Gynecology, College of Medicine, University of Kentucky, Lexington, KY 40508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Arts and Science, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3757-2822","authenticated-orcid":false,"given":"Kristen S.","family":"Hill","sequence":"additional","affiliation":[{"name":"Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7272-2120","authenticated-orcid":false,"given":"Melissa A.","family":"Fath","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5119-2474","authenticated-orcid":false,"given":"Derek B.","family":"Allison","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, College of Medicine, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.","family":"Richards","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Arts and Science, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill M.","family":"Kolesar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"ref_1","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J. 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