Highly efficient healing of critical sized articular cartilage defect in situ using a chemically nucleoside-modified mRNA-enhanced cell therapy

Critical sized cartilage defects heal poorly and MSC-based therapies holds promise functional cartilage regeneration either used alone or in combination with growth factors. However, Recombinant protein growth factors were proven to have minimal benefits while to have adverse side effects and high cost. Nonviral mRNA delivery provides a promising, alternative approach to delivering therapeutic proteins within defect lesion for an extended period of time. Despite successful therapeutic outcome in bone and other vascularized tissues, the therapeutic application of mRNA in poorly vascularized tissues such as cartilage is still facing many challenges and rarely studied. We report here using chemically modified messenger RNA encoding TGF-β3(TGF-β3 cmRNA) to enhance the therapeutic efficacy of BMSCs to efficient repair of cartilage defect. Local administration of TGF-β3 cmRNA enhanced BMSCs therapy restored critical-sized cartilage defects in situ in a rat model within 6 weeks with structural and molecular markers similar to its nature counterparts. In addition, the development of osteoarthritis caused by cartilage damage was prevented by this mRNA-enhanced BMSCs therapy evidenced by minimal late-stage OA pharmacological presentations. This novel mRNA enhanced-MSC technology extend the development of new therapeutic approaches for treating functional cartilage repair. ### Competing Interest Statement YY received the research funding from:National Nature Science Foundation of China (82002355), Shenzhen Institute of Synthetic Biology Scientific Research Program (Grant No. DWKF20190010, JCHZ20200005), FC received the research funding from: the Shenzhen Institutes of Advanced Technology Innovation Program for Excellent Young Researchers (Y9G075), GeneHeal Medicine-SIAT mRNA Regenerative Medicine Laboratory (E1Z124) . LZ received the research funding from: the National Natural Science Foundation of China [81660364, 81760343], Jiangxi Provincial Department of Education Research Program Major Project (171352), Science and Technology Planning Project of Jiangxi Health Commission (20191025, 202130131). XZ received the research funding National Nature Science Foundation of China (32071341). GW, JH, FY are employee at Gene Heal Medicine, a privately owned company developing mRNA therapeutics.All others have no potential conflict of interest.