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Silencing-mediated enhancement of osteogenic differentiation by supramolecular ternary siRNA polyplexes comprising biocleavable cationic polyrotaxanes and anionic fusogenic peptides

Abstract

Gene silencing of noggin by small interfering RNA (siRNA) is a promising approach for the treatment of bone defects, because noggin deactivates bone morphogenetic protein-2 (BMP-2) and suppresses osteogenic differentiation. Here, we demonstrated the silencing of the noggin gene by siRNA polyplexes composed of noggin-targeted siRNA and biocleavable cationic polyrotaxanes (DMAE-SS-PRX). To improve the endosomal escape efficiencies of the DMAE-SS-PRX/siRNA polyplexes, anionic and fusogenic GALA peptides were integrated onto the DMAE-SS-PRX/siRNA polyplexes via simple electrostatic interaction. The formation of ternary complexes was confirmed by gel electrophoresis, dynamic light scattering, and zeta-potential measurements. Although the association of GALA peptides with the DMAE-SS-PRX/siRNA polyplexes did not remarkably affect the cellular uptake efficiency of siRNA, the endosomal escape efficiency was remarkably increased for GALA/DMAE-SS-PRX/siRNA ternary polyplexes because of the endosomal and lysosomal membrane destabilization by GALA peptides. Consequently, GALA/DMAE-SS-PRX/siRNA ternary polyplexes showed significantly higher gene silencing efficiency against noggin and enhanced the BMP-2-mediated osteogenic differentiation efficiency. Therefore, we concluded that GALA/DMAE-SS-PRX/siRNA ternary polyplexes can be effective siRNA carriers for suppressing the expression of specific endogenous genes. Consequently, we believe that more practical approach in vivo will be the combined use of BMP-2 and GALA/DMAE-SS-PRX/siRNA ternary polyplexes, because it will improve the efficacy of bone regeneration therapy.

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Publication details

The article was received on 27 Nov 2017, accepted on 09 Jan 2018 and first published on 09 Jan 2018


Article type: Paper
DOI: 10.1039/C7BM01100H
Citation: Biomater. Sci., 2018, Accepted Manuscript
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    Silencing-mediated enhancement of osteogenic differentiation by supramolecular ternary siRNA polyplexes comprising biocleavable cationic polyrotaxanes and anionic fusogenic peptides

    T. Inada, A. Tamura, M. Terauchi, S. Yamaguchi and N. Yui, Biomater. Sci., 2018, Accepted Manuscript , DOI: 10.1039/C7BM01100H

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