Human BMP4 mRNA Encapsulated in Lipid Nanoparticle Delayed Cartilage Degeneration but Has a Limited Enhancement Effect on Bone Healing in Aged Mice

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 sustain-release delivery, few have translated into clinical therapies due to safety concerns. Bone morphogenetic proteins belong to the TGFβ 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/LNP) can promote bone and cartilage repair. Our results demonstrated that hBMP4/LNP promoted limited new bone formation only at 2 weeks after creation of defect in critical-sized calvarial bone defect in aged mice at 50µg dose when delivered using fibrin sealant hydrogel as revealed by micro-CT and histology. However, intra-articular injection (IA) of lower doses (2.5 and 5µg) in aged mice knee joints prevented cartilage loss as demonstrated by micro-CT, decreased OARSI histology scores and improved cartilage specific matrix COL2. HBMP4/LNP treatment showed a trend of pain alleviation and did not change serum hyaluronic acid levels. In conclusion, human BMP4 mRNA encapsulated in lipid nanoparticle improved cartilage repair & delay cartilage degeneration in age mice while having a limited effect on bone healing, even a higher dosage. These results suggest that hBMP4 mRNA encapsulated with lipid nanoparticle represents a promising treatment for age-related OA.