De Paula Daniel, Bentley M Vitória L B, Mahato Ram I
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP Brazil.
RNA. 2007 Apr;13(4):431-56. doi: 10.1261/rna.459807. Epub 2007 Feb 28.
RNA interference (RNAi) is an evolutionarily conserved process by which double-stranded small interfering RNA (siRNA) induces sequence-specific, post-transcriptional gene silencing. Unlike other mRNA targeting strategies, RNAi takes advantage of the physiological gene silencing machinery. The potential use of siRNA as therapeutic agents has attracted great attention as a novel approach for treating severe and chronic diseases. RNAi can be achieved by either delivery of chemically synthesized siRNAs or endogenous expression of small hairpin RNA, siRNA, and microRNA (miRNA). However, the relatively high dose of siRNA required for gene silencing limits its therapeutic applications. This review discusses several strategies to improve therapeutic efficacy as well as to abrogate off-target effects and immunostimulation caused by siRNAs. There is an in-depth discussion on various issues related to the (1) mechanisms of RNAi, (2) methods of siRNA production, (3) barriers to RNAi-based therapies, (4) biodistribution, (5) design of siRNA molecules, (6) chemical modification and bioconjugation, (7) complex formation with lipids and polymers, (8) encapsulation into lipid particles, and (9) target specificity for enhanced therapeutic effectiveness.
RNA干扰（RNAi）是一种进化上保守的过程，双链小干扰RNA（siRNA）通过该过程诱导序列特异性的转录后基因沉默。与其他mRNA靶向策略不同，RNAi利用了生理基因沉默机制。siRNA作为治疗剂的潜在用途作为一种治疗严重和慢性疾病的新方法已引起了极大关注。RNAi可以通过化学合成的siRNA的递送或小发夹RNA、siRNA和微小RNA（miRNA）的内源性表达来实现。然而，基因沉默所需的相对高剂量的siRNA限制了其治疗应用。本综述讨论了几种提高治疗效果以及消除由siRNA引起的脱靶效应和免疫刺激的策略。对与以下方面相关的各种问题进行了深入讨论：（1）RNAi机制，（2）siRNA生产方法，（3）基于RNAi的疗法的障碍，（4）生物分布，（5）siRNA分子设计，（6）化学修饰和生物共轭，（7）与脂质和聚合物形成复合物，（8）封装到脂质颗粒中，以及（9）增强治疗效果的靶标特异性。
