VEGF and Runx2 mRNA Delivered by Nanomicelle Accelerate Bone Regeneration

Researchers here report on progress in their program of demonstrating that upregulation of VEGF and Runx2 in combination can accelerate bone regrowth. In this animal study the researchers employed a therapy based on delivery of messenger RNA (mRNA) encapsulated in nanomicelle carrier particles formed from polyethylene glycol and polyamino acid. This produces short-term, localized expression of VEGF and Runx2 in the injured bone tissue when injected directly, and is a suitable basis for translation to clinical use, where the carrier might be swapped out for one of the more established lipid nanoparticle carriers.

Bone defects remain a challenge today. In addition to osteogenic activation, the crucial role of angiogenesis has also gained attention. In particular, vascular endothelial growth factor (VEGF) is likely to play a significant role in bone regeneration, not only to restore blood supply but also to be directly involved in the osteogenic differentiation of mesenchymal stem cells. In this study, to produce additive angiogenic-osteogenic effects in the process of bone regeneration, VEGF and Runt-related transcription factor 2 (Runx2), an essential transcription factor for osteogenic differentiation, were coadministered with messenger RNAs (mRNAs) to bone defects in the rat mandible.

The mRNAs were administered to a bone defect prepared in the rat mandible using our original cationic polymer-based carrier, the polyplex nanomicelle. The bone regeneration was evaluated by micro-computerized tomography (╬╝CT) imaging, and histologic analyses.

Osteogenic markers such as osteocalcin (Ocn) and osteopontin (Opn) were significantly upregulated after mRNA transfection. VEGF mRNA was revealed to have a distinct osteoblastic function similar to that of Runx2 mRNA, and the combined use of the two mRNAs resulted in further upregulation of the markers. After in vivo administration into the bone defect, the two mRNAs induced significant enhancement of bone regeneration with increased bone mineralization. Histological analyses using antibodies against CD31, ALP, or OCN revealed that the mRNAs induced the upregulation of osteogenic markers in the defect, together with increased vessel formation, leading to rapid bone formation.


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