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Purpose: Gene therapies via Noggin small interfering (si)RNA ( siNoggin ) and bone morphogenetic protein ( BMP ) -2 plasmid DNA ( pBMP-2 ) may be promising strategies for bone repair/regeneration, but their ideal delivery vectors, efficacy difference, and underlying mechanisms have not been explored, so these issues were probed here. Methods: This study used lipopolysaccharide-amine nanopolymersomes (LNPs), an efficient cytosolic delivery vector developed by the research team, to mediate siNoggin and pBMP-2 to transfect MC3T3-E1 cells, respectively. The cytotoxicity, cell uptake, and gene knockdown efficiency of siNoggin -loaded LNPs (LNPs/ siNoggin ) were studied, then the osteogenic-differentiation efficacy of MC3T3-E1 cells treated by LNPs/ pBMP-2 and LNPs/ siNoggin , respectively, were compared by measuring the expression of osteogenesis-related genes and proteins, alkaline phosphatase (ALP) activity, and mineralization of the extracellular matrix at all osteogenic stages. Finally, the possible signaling pathways of the two treatments were explored. Results: LNPs delivered siNoggin into cells efficiently to silence 50% of Noggin expression without obvious cytotoxicity. LNPs/ siNoggin and LNPs/ pBMP-2 enhanced the osteogenic differentiation of MC3T3 E1 cells, but LNPs/ siNoggin was better than LNPs/ pBMP-2 . BMP/Mothers against decapentaplegic homolog (Smad) and glycogen synthase kinase (GSK)-3β/β-catenin signaling pathways appeared to be involved in osteogenic differentiation induced by LNPs/ siNoggin , but GSK-3β/β-catenin was not stimulated upon LNPs/ pBMP-2 treatment. Conclusion: LNPs are safe and efficient delivery vectors for DNA and RNA, which may find wide applications in gene therapy. siNoggin treatment may be a more efficient strategy to enhance osteogenic differentiation than pBMP-2 treatment. LNPs loaded with siNoggin and/or pBMP-2 may provide new opportunities for the repair and regeneration of bone.

international journal of nanomedicine

&lt;p&gt;Comparison of osteogenic differentiation induced by &lt;em&gt;siNoggin&lt;/em&gt; and &lt;em&gt;pBMP-2&lt;/em&gt; delivered by lipopolysaccharide-amine nanopolymersomes and underlying molecular mechanisms&lt;/p&gt;