Synergistic Osteogenesis After Co‐Administration of cmRNAs Encoding BMP‐2 and BMP‐7 Utilizing a Transcript‐Activated Matrix

Abstract Bone morphogenetic proteins ‐2 and ‐7 (BMP‐2 and BMP‐7) are effective in treating large bone defects, but the required doses are high, resulting in side effects and elevated costs. Previously, this work has demonstrated that a chemically modified messenger RNA (cmRNA) coding for BMP‐2 induced rapid and reliable healing until consolidation in a bone segmental defect in rats. Here, this work shows that the simultaneous transfer of BMP‐2 and BMP‐7 cmRNAs to stem cells leads to increased osteogenic gene expression, extracellular matrix deposition, and mineralization, compared to single or sequential delivery of these cmRNAs. Using a murine model of ectopic ossification, this work finds that dual BMP‐2/BMP‐7 cmRNA delivery using collagen‐hydroxyapatite scaffolds, designed specifically for bone repair, ensured local BMP‐2 and ‐7 expression with abundant osteogenesis in the absence of adverse effects. This confirms the superior osteogenic potency achieved by local, controlled dual delivery of cmRNAs encoding BMP‐2 and BMP‐7, further enhancing the potential of this highly translatable technology for promoting bone healing.