Knocking down barriers: advances in siRNA delivery.
Knocking down barriers: advances in siRNA delivery.
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DOI：
10.1038/nrd2742
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发表时间：
2009-03
期刊：
影响因子：
--
通讯作者：
Anderson DG
中科院分区：
文献类型：
--
作者：
Whitehead KA;Langer R;Anderson DG
RNA干扰(RNAi)是真核细胞中的一种基本途径，序列特异性小干扰RNA(SiRNA)通过破坏互补的mRNA来沉默基因。RNAi是一种重要的治疗工具，可用于沉默异常的内源性基因或敲除感染生物增殖所必需的基因。递送仍然是RNAi技术治疗应用的核心挑战。在siRNA能够在靶细胞的细胞质中发挥作用之前，它必须在不经历清除或降解的情况下通过体内运输到靶部位。目前，最有效的合成的、非病毒的siRNA递送剂是脂类、类脂材料和聚合物。各种阳离子制剂，包括稳定的核酸-脂质颗粒、类脂类化合物、环糊精聚合物和聚乙烯亚胺聚合物，已经被用来在不引起明显毒性的情况下成功地在哺乳动物体内实现系统递送siRNA。递送剂与siRNA的直接偶联可以促进递送。例如，胆固醇修饰的siRNA能够靶向肝脏。RNAi疗法已经进入临床，正在进行研究，以确定siRNA对几种疾病的疗效，包括老年性黄斑变性和呼吸道合胞病毒。展望未来，密切关注siRNA潜在的非特异性免疫刺激作用将是重要的。对siRNA的修饰可以用来最大限度地减少对免疫系统的刺激，必须更加重视进行适当的控制，以确保治疗效果具有序列特异性。RNA干扰作为疾病预防和治疗的一种治疗策略具有巨大的潜力，但到目前为止，由于缺乏安全和有效的递送技术，其使用一直受到阻碍。在他们的综述中，Anderson和他的同事讨论了与小干扰RNA传递相关的挑战，并强调了有前景的新型合成传递剂。在诺贝尔奖获奖的RNA干扰(RNAi)发现以来的10年里，数十亿美元被投入到人类基因沉默的治疗应用上。今天，正在进行的治疗老年性黄斑变性和呼吸道合胞病毒的临床试验中有很有希望的数据。然而，尽管取得了这些早期的成功，但RNAi疗法在疾病预防和治疗中的广泛使用需要开发临床适用、安全和有效的药物输送载体。在这里，我们提供了RNAi治疗的最新进展，并重点介绍了用于包裹和细胞内递送核酸的新型合成材料。
RNA interference (RNAi) is a fundamental pathway in eukaryotic cells by which sequence-specific small interfering RNA (siRNA) is able to silence genes through the destruction of complementary mRNA. RNAi is an important therapeutic tool that can be used to silence aberrant endogenous genes or to knockdown genes essential to the proliferation of infectious organisms. Delivery remains the central challenge to the therapeutic application of RNAi technology. Before siRNA can take effect in the cytoplasm of a target cell, it must be transported through the body to the target site without undergoing clearance or degradation. Currently, the most effective synthetic, non-viral delivery agents of siRNA are lipids, lipid-like materials and polymers. Various cationic agents including stable nucleic acid–lipid particles, lipidoids, cyclodextrin polymers and polyethyleneimine polymers have been used to achieve the successful systemic delivery of siRNA in mammals without inducing significant toxicity. Direct conjugation of delivery agents to siRNA can facilitate delivery. For example, cholesterol-modified siRNA enables targeting to the liver. RNAi therapeutics have progressed to the clinic, where studies are being conducted to determine siRNA efficacy in treating several diseases, including age-related macular degeneration and respiratory syncytial virus. Moving forward, it will be important to pay close attention to the potential nonspecific immunostimulatory effects of siRNA. Modifications to siRNA can be used to minimize stimulation of the immune system, and an increased emphasis must be placed on performing proper controls to ensure that therapeutic effects are sequence-specific. RNA interference holds vast potential as a therapeutic strategy for both disease prevention and treatment, but its use has so far been hampered by a lack of safe and effective delivery techniques. In their Review, Anderson and colleagues discuss the challenges associated with small interfering RNA delivery and highlight promising novel synthetic delivery agents. In the 10 years that have passed since the Nobel prize-winning discovery of RNA interference (RNAi), billions of dollars have been invested in the therapeutic application of gene silencing in humans. Today, there are promising data from ongoing clinical trials for the treatment of age-related macular degeneration and respiratory syncytial virus. Despite these early successes, however, the widespread use of RNAi therapeutics for disease prevention and treatment requires the development of clinically suitable, safe and effective drug delivery vehicles. Here, we provide an update on the progress of RNAi therapeutics and highlight novel synthetic materials for the encapsulation and intracellular delivery of nucleic acids.
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