Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 19 S Manassas, RM 224, Memphis, Tennessee 38103-3308, USA.
Pharm Res. 2011 Dec;28(12):2996-3015. doi: 10.1007/s11095-011-0608-1. Epub 2011 Oct 28.
RNA interference (RNAi) strategies include double-stranded RNA (dsRNA), small interfering RNA (siRNA), short hairpin RNA (shRNA), and microRNA (miRNA). As this is a highly specific technique, efforts have been made to utilize RNAi towards potential knock down of disease-causing genes in a targeted fashion. RNAi has the potential to selectively inhibit gene expression by degrading or blocking the translation of the target mRNA. However, delivering these RNAs to specific cells presents a significant challenge. Some of these challenges result from the necessity of traversing the circulatory system while avoiding kidney filtration, degradation by endonucleases, aggregation with serum proteins, and uptake by phagocytes. Further, non-specific delivery may result in side-effects, including the activation of immune response. We discuss the challenges in the systemic delivery to target cells, cellular uptake, endosomal release and intracellular transport of RNAi drugs and recent progress in overcoming these barriers. We also discuss approaches that increase the specificity and metabolic stability and reduce the off-target effects of RNAi strategy.
RNA 干扰 (RNAi) 策略包括双链 RNA(dsRNA)、小干扰 RNA(siRNA)、短发夹 RNA(shRNA) 和 microRNA(miRNA)。由于这是一种高度特异的技术，人们一直致力于利用 RNAi 有针对性地敲低致病基因。RNAi 通过降解或阻断靶 mRNA 的翻译具有选择性抑制基因表达的潜力。然而，将这些 RNA 递送到特定的细胞是一个巨大的挑战。其中一些挑战是由于必须穿过循环系统，同时避免肾脏过滤、内切酶降解、与血清蛋白聚集以及被吞噬细胞摄取。此外，非特异性递送可能会导致副作用，包括免疫反应的激活。我们讨论了将 RNAi 药物递送到靶细胞、细胞摄取、内涵体释放和细胞内运输中的系统性挑战以及克服这些障碍的最新进展。我们还讨论了增加 RNAi 策略的特异性和代谢稳定性并降低脱靶效应的方法。
