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β-catenin mRNA encapsulated in SM-102 lipid nanoparticles enhances bone formation in a murine tibia fracture repair model

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Bioactive Materials 2024年第9期39卷 273-286页

作者： Anna laura Nelson Chiara Mancino Xueqin Gao Joshua AChoe laura chubb Katherine Williams Molly Czachor Ralph Marcucio Francesca Taraballi John P.Cooke Johnny Huard Chelsea Bahney Nicole Ehrhart Steadman Philippon Research Institute(SPRI) Center for Regenerative and Personalized MedicineVailCOUSA Houston Methodist Research Institute Center for Musculoskeletal RegenerationHouston TXUSA University of Wisconsin-Madison Department of Orthopedics and RehabilitationDepartment of Biomedical EngineeringMedical Scientist Training ProgramMadisonWIUSA Colorado State University School of Biomedical EngineeringFort Collins COUSA Colorado State University Department of Clinical SciencesFort Collins COUSA Colorado State University Department of MicrobiologyImmunologyand PathologyFort CollinsCOUSA Houston Methodist Research Institute Center for RNA TherapeuticsDepartment of Cardiovascular SciencesHoustonTXUSA University of Californi1 San Francisco(UCSF)Orthopaedic Trauma InstituteSan FranciscoCAUSA

Fractures continue to be a global economic burden as there are currently no osteoanabolic drugs approved to accelerate fracture *** this study,we aimed to develop an osteoanabolic therapy which activates the Wnt/β-catenin pathway,a molecular driver of endochondral *** hypothesize that using an mRNAbased therapeutic encodingβ-catenin could promote cartilage to bone transformation formation by activating the canonical Wnt signaling pathway in *** optimize a delivery platform built on recent advancements in liposomal technologies,two FDA-approved ionizable phospholipids,DLin-MC3-DMA(MC3)and SM-102,were used to fabricate unique ionizable lipid nanoparticle(LNP)formulations and then tested for transfection efficacy both in vitro and in a murine tibia fracture *** firefly luciferase mRNA as a reporter gene to track and quantify transfection,SM-102 LNPs showed enhanced transfection efficacy in vitro and prolonged transfection,minimal fracture interference and no localized inflammatory response in vivo over MC3 *** generatedβ-cateninGOF mRNA encapsulated in SM-102 LNPs(SM-102-β-cateninGOF mRNA)showed bioactivity in vitro through upregulation of downstream canonical Wnt genes,axin2 and *** testing SM-102-β-cateninGOF mRNA therapeutic in a murine tibia fracture model,histomorphometric analysis showed increased bone and decreased cartilage composition with the 45μg concentration at 2 weeks post-fracture.μCT testing confirmed that SM-102-β-cateninGOF mRNA promoted bone formation in vivo,revealing significantly more bone volume over total volume in the 45μg ***,we generated a novel mRNA-based therapeutic encoding aβ-catenin mRNA and optimized an SM-102-based LNP to maximize transfection efficacy with a localized delivery.

关键词： Gene therapy Fracture healing Lipid nanoparticles mRNA Canonical Wnt

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