BMP-7 mRNA delivered by Fibrin-CaP scaffolds activates osteogenic programs in vivo as evidenced by transcriptomic and...

Two recombinant bone morphogenetic proteins (BMP-2 and BMP-7) have received FDA approval for bone-related therapies. However, their clinical performance is limited by high costs, the need for supraphysiological doses, and adverse side effects. Here, we describe a chemically modified mRNA (cmRNA) encoding BMP-7 that promotes osteogenesis and functional ossification. The BMP-7 cmRNA is delivered using optimized lipid vectors and a composite fibrin-calcium phosphate scaffold. Among several lipids evaluated, two previously unexplored lipids efficiently condense mRNA and mediate its in vivo delivery. Transfer of BMP-7 cmRNA lipoplexes to human mesenchymal stromal cells activates intracellular vesicle transport and cytoskeletal remodeling, and regulates extracellular matrix production and calcium-associated processes. These responses were accompanied by robust mineralization and activation of key osteogenic pathways. In vivo, BMP-7 mRNA-activated scaffolds promote the formation of ossified tissue, with the highest dose yielding the largest ectopic bony growth. We further observe concurrent angiogenesis and neurogenesis, demonstrating coordinated tissue regeneration. This platform enables effective in vivo mRNA delivery for bone healing and can be applied to other tissues, facilitating the development of mRNA therapeutics in regenerative medicine.