Akhtar Saghir, Benter Ibrahim
SA Pharma, Vesey Road 1, Sutton Coldfield, West Midlands, B73 5NP, United Kingdom.
Adv Drug Deliv Rev. 2007 Mar 30;59(2-3):164-82. doi: 10.1016/j.addr.2007.03.010. Epub 2007 Mar 21.
RNA interference (RNAi) is an evolutionary conserved cellular process for the regulation of gene expression. In mammalian cells, RNAi is induced via short (21-23 nt) duplexes of RNA, termed small interfering RNA (siRNA), that can elicit highly sequence-specific gene silencing. However, synthetic siRNA duplexes are polyanionic macromolecules that do not readily enter cells and typically require the use of a delivery vector for effective gene silencing in vitro and in vivo. Choice of delivery system is usually made on its ability to enhance cellular uptake of siRNA. However, recent gene expression profiling (toxicogenomics) studies have shown that separate from their effects on cellular uptake, delivery systems can also elicit wide ranging gene changes in target cells that may impact on the 'off-target' effects of siRNA. Furthermore, if delivery systems also alter the expression of genes targeted for silencing, then siRNA activity may be compromised or enhanced depending on whether the target gene is up-regulated or down-regulated respectively. Citing recent examples from the literature, this article therefore reviews the toxicogenomics of non-viral delivery systems and highlights the importance of understanding the genomic signature of siRNA delivery reagents in terms of their impact on gene silencing activity and specificity. Such information will be essential in the selection of optimally acting siRNA-delivery system combinations for the many applications of RNA interference.
RNA干扰（RNAi）是一种进化保守的细胞过程，用于调节基因表达。在哺乳动物细胞中，RNAi通过短（21 - 23个核苷酸）的RNA双链体诱导产生，称为小干扰RNA（siRNA），它能引发高度序列特异性的基因沉默。然而，合成的siRNA双链体是多阴离子大分子，不易进入细胞，通常需要使用递送载体才能在体外和体内实现有效的基因沉默。递送系统的选择通常基于其增强细胞摄取siRNA的能力。然而，最近的基因表达谱分析（毒理基因组学）研究表明，除了对细胞摄取的影响外，递送系统还能在靶细胞中引发广泛的基因变化，这可能会影响siRNA的“脱靶”效应。此外，如果递送系统还改变了靶向沉默基因的表达，那么siRNA的活性可能会受到损害或增强，这取决于靶基因是分别被上调还是下调。本文引用文献中的最新例子，综述了非病毒递送系统的毒理基因组学，并强调了了解siRNA递送试剂的基因组特征对其基因沉默活性和特异性影响的重要性。这些信息对于为RNA干扰的众多应用选择最佳作用的siRNA - 递送系统组合至关重要。
