Effective gene delivery of shBMP-9 using polyethyleneimine-based core-shell nanoparticles in an animal model of insulin resistance
Effective gene delivery of shBMP-9 using polyethyleneimine-based core-shell nanoparticles in an animal model of insulin resistance
复制标题
在胰岛素抵抗动物模型中使用基于聚乙烯亚胺的核壳纳米颗粒有效基因递送 shBMP-9
DOI：
10.1039/c8nr08193j
复制
发表时间：
2019-01-28
期刊：
影响因子：
6.7
通讯作者：
Yang, Gangyi
中科院分区：
文献类型：
--
作者：
Jia, Yanjun;Niu, Dechao;Yang, Gangyi
骨形态发生蛋白(BMP)-9与胰岛素抵抗和2型糖尿病有关。然而，缺乏在体内传递外源BMP-9基因的方法。本研究以聚乙烯亚胺（PEI）基核壳纳米颗粒（PCNs）作为基因传递载体，构建了一种基因传递系统，并研究了其传递shBMP-9基因的有效性和安全性。PCNs具有明确的核-壳纳米结构，具有疏水性聚合物芯和致密的PEI壳，具有均匀的粒径和高正电荷表面。体外评价表明pcn对外源基因的负载能力高，对肝细胞的细胞毒性低。PCNs/ penr -shBMP9复合物的转染效率高于商用脂质体2000/shBMP9。体内研究表明，与转染PCNs/ penr - shbmp9相比，转染PCNs/ penr - shbmp9可显著降低肝脏BMP9的表达。在高脂饮食（HFD）喂养下，PCNs/ penr - shbmp9小鼠表现出加重的葡萄糖和胰岛素耐受性。在分子水平上，PCNs/ penr - shbmp9小鼠的PEPCK蛋白水平升高，InsR和Akt磷酸化水平低于penr - shbmp9小鼠。这些结果表明PCNs/ penr - shbmp9在体内的生物学效应比penr - shbmp9更有效。因此，以聚乙烯亚胺（PEI）为基础的核壳纳米颗粒是一种安全有效的基因载体，具有广阔的应用前景。
Bone morphogenetic protein (BMP)-9 has been associated with insulin resistance and type 2 diabetes mellitus. However, methods for delivering exogenous BMP-9 genes in vivo are lacking. In this study, we developed a gene delivery system using polyethyleneimine (PEI)-based core-shell nanoparticles (PCNs) as gene delivery carriers, and investigated the effectiveness and safety for delivery of the shBMP-9 gene. PCNs possessed a well-defined core-shell nanostructure with hydrophobic polymer cores and dense PEI shells of uniform particle size and highly positively charged surfaces. In vitro evaluation suggested that PCNs had high loading capacity for exogenous genes and low cytotoxicity toward hepatocytes. The transfection efficiency of PCNs/pENTR-shBMP9 complexes was higher than that of commercial lipofectamine 2000/shBMP9. In vivo studies showed that PCNs/pENTR-shBMP9 transfection led to a significant decrease in hepatic BMP9 expression compared with pENTR-shBMP9 transfection. Under high fat diet (HFD) feeding, PCNs/pENTR-shBMP9 mice exhibited aggravated glucose and insulin tolerance. At a molecular level, PCNs/pENTR-shBMP9 mice displayed elevated PEPCK protein levels and lower levels of InsR and Akt phosphorylation than pENTR-shBMP9 mice. These results suggest that the biological effects of PCNs/pENTR-shBMP9 in vivo are much more effective than those of pENTR-shBMP9. Therefore, the polyethyleneimine (PEI)-based core-shell nanoparticle can be applied as promising nanocarriers for effective and safe gene delivery.