A silencing-mediated enhancement of osteogenic differentiation by supramolecular ternary siRNA polyplexes comprising biocleavable cationic polyrotaxanes and anionic fusogenic peptides†,Biomaterials Science

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A silencing-mediated enhancement of osteogenic differentiation by supramolecular ternary siRNA polyplexes comprising biocleavable cationic polyrotaxanes and anionic fusogenic peptides†
Biomaterials Science ( IF 5.8 ) Pub Date : 2018-01-09 00:00:00 , DOI: 10.1039/c7bm01100h
Takasuke Inada _{1,

2,

3,

4,

5} , Atsushi Tamura _{3,

5,

6,

7,

8} , Masahiko Terauchi _{1,

2,

3,

4,

5} , Satoshi Yamaguchi _{1,

2,

3,

4,

5} , Nobuhiko Yui _{3,

5,

6,

7,

8}

Affiliation

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 interactions. 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 a 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.

中文翻译：

包含生物可裂解阳离子聚轮烷和阴离子融合肽的超分子三元siRNA多聚体沉默介导的成骨分化增强†

通过小干扰RNA（siRNA）使头蛋白基因沉默是一种有前景的骨缺损治疗方法，因为头蛋白可以使骨形态发生蛋白2（BMP-2）失活并抑制成骨细胞分化。在这里，我们展示了由noggin靶向的siRNA和可生物裂解的阳离子聚轮烷（DMAE-SS-PRX）组成的siRNA polyplex对noggin基因的沉默。为了提高DMAE-SS-PRX / siRNA多聚体的内体逃逸效率，阴离子和融合GALA肽可通过以下途径整合到DMAE-SS-PRX / siRNA多聚体中简单的静电相互作用。通过凝胶电泳，动态光散射和ζ电势测量证实了三元复合物的形成。尽管GALA肽与DMAE-SS-PRX / siRNA多聚体的结合不会显着影响siRNA的细胞吸收效率，但由于内体，GALA / DMAE-SS-PRX / siRNA三元多聚体的内体逃逸效率显着提高以及GALA肽引起的溶酶体膜失稳。因此，GALA / DMAE-SS-PRX / siRNA三元复合物显着提高了针对头蛋白的基因沉默效率，并增强了BMP-2介导的成骨分化效率。因此，我们得出结论，GALA / DMAE-SS-PRX / siRNA三元复合物可以是抑制特定内源基因表达的有效siRNA载体。体内将联合使用BMP-2和GALA / DMAE-SS-PRX / siRNA三元复合物，因为它将提高骨再生治疗的功效。

更新日期：2018-01-09

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