{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T05:04:19Z","timestamp":1780463059117,"version":"3.54.1"},"reference-count":57,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Musculoskeletal Regeneration Partnership Fund by Mary Sue and Michael Shannon and the Donna Giordano Family.","award":["3024"],"award-info":[{"award-number":["3024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JFB"],"abstract":"<jats:p>Segmental bone defects and age-related osteoarthritis (OA) are clinically challenging in terms of treatment. Although preclinical studies have demonstrated efficacy for bone defect healing and OA using ex vivo gene therapy or biomaterial sustained-release delivery, few such treatments have translated into clinical therapies due to safety concerns. Bone morphogenetic proteins belong to the transforming growth factor \u03b2 (TGF\u03b2) superfamily and are effective in bone and cartilage regeneration\/repair. Among BMPs, BMP4 is not only effective in promoting bone and cartilage repair but also promotes stem cell renewal potential and exhibits anti-aging effects. Therefore, the aim of this study is to investigate whether human BMP4 mRNA encapsulated in lipid nanoparticles (hBMP4 mRNA\/LNP) can promote bone and cartilage repair. In vitro data demonstrated that hBMP4 mRNA\/LNP-treated human MSCs secreted BMP4 protein, as detected by ELISA, and enhanced osteogenic differentiation. In vivo results demonstrated that hBMP4 mRNA\/LNP at a 50 \u00b5g dose promoted limited new bone formation only at 2 weeks after creation of defect in critical-sized calvarial bone defects in aged mice when delivered using fibrin sealant hydrogel, as revealed by micro-CT and histology. However, intra-articular injection (IA) of lower doses (2.5 and 5 \u00b5g) in aged mice knee joints prevented cartilage loss, as demonstrated by micro-CT; decreased OARSI histology scores; and improved cartilage-specific matrix COL2. hBMP4 mRNA\/LNP at a 5 \u03bcg dose significantly increased SOX9+ cells per normalized cartilage area as well as the percentage of SOX9+ cells in the cartilage area. hBMP4 mRNA\/LNP treatment showed a trend of pain alleviation and did not change serum hyaluronic acid levels. In conclusion, human BMP4 mRNA encapsulated in lipid nanoparticles improved cartilage repair and delayed cartilage degeneration in aged mice, while having a limited effect on bone healing, even at a higher dosage. These results suggest that hBMP4 mRNA encapsulated with lipid nanoparticles represents a promising treatment for age-related OA.<\/jats:p>","DOI":"10.3390\/jfb17060273","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T17:11:01Z","timestamp":1780333861000},"page":"273","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Human BMP4 mRNA Encapsulated in Lipid Nanoparticle for Bone and Articular Cartilage Repair in Aged Mice"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5833-1548","authenticated-orcid":false,"given":"Xueqin","family":"Gao","sequence":"first","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuokui","family":"Xiao","sequence":"additional","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthieu","family":"Huard","sequence":"additional","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1370-4974","authenticated-orcid":false,"given":"Keisuke","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aryn","family":"Cummings","sequence":"additional","affiliation":[{"name":"Laboratory Animal Resources, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britney S.","family":"Force","sequence":"additional","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongye","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Regeneration, Houston Methodist Academic Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Mancino","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Regeneration, Houston Methodist Academic Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0033-9138","authenticated-orcid":false,"given":"John P.","family":"Cooke","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Regeneration, Houston Methodist Academic Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4959-1169","authenticated-orcid":false,"given":"Francesca","family":"Taraballi","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Regeneration, Houston Methodist Academic Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0358-3331","authenticated-orcid":false,"given":"Marc J.","family":"Philippon","sequence":"additional","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnny","family":"Huard","sequence":"additional","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1016\/S0140-6736(19)30417-9","article-title":"Osteoarthritis","volume":"393","author":"Hunter","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1007\/s10067-025-07761-w","article-title":"Burden of osteoarthritis in North Africa and Middle East from 1990 to 2021: Findings from the Global Burden of Disease 2021 study","volume":"45","author":"Rashidi","year":"2025","journal-title":"Clin. 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