Engineering active siRNA therapeutics.
Engineering active siRNA therapeutics.
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设计活性 siRNA 疗法。
DOI：
10.1111/j.1742-4658.2010.07902.x
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Walton,SPatrick
中科院分区：
文献类型：
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作者：
Walton,SPatrick
RNA干扰(RNAi)的发现导致了开发短干扰RNA(SiRNAs)的热潮，以用于各种应用，特别是在治疗方面。基于RNAi的疗法的一个特别优势是它们利用了真核细胞中现有的基因表达调控机制。因此，siRNAs具有调节细胞功能的潜力，具有极高的特异性和有限的副作用。然而，siRNAs作为治疗学的发展将需要继续研究，重点放在过程中的关键瓶颈。为了在体内启动RNAi，siRNAs首先被封装到通常是阳离子的递送载体中，以平衡电荷，并且性质是类脂或聚合物的。与其他药物一样，载体-siRNA复合体要么直接给药到感兴趣的部位(例如通过注射)，以最大限度地减少向非靶向组织的贩运，并最大限度地提高药物的局部浓度，要么通过血液(静脉)或胃肠道系统(口服)给药，以简化给药。一旦被运送到感兴趣的组织，载体-siRNA复合体必须到达靶细胞，并穿过质膜进入细胞质。在这一点上，必须从载体中释放siRNA才能被RNAi机制识别。
The discovery of RNA interference (RNAi) has led to a rush to develop short interfering RNAs (siRNAs) for a variety of applications, especially for therapeutics. A particular advantage of RNAi-based therapeutics is that they utilize the existing regulatory machinery of gene expression in eukaryotic cells. For this reason, siRNAs have the potential to modulate cell function with exquisite specificity and limited side effects. Nonetheless, the development of siRNAs as therapeutics will require continued research focused on the critical bottlenecks in the process.To initiate RNAi in vivo, siRNAs are first encapsulated into a delivery vehicle that is typically cationic, to balance charge, and either lipid-like or polymeric in nature. As with other drugs, the vehicle–siRNA complexes are either administered directly to the site of interest (eg by injection) to minimize trafficking to nontargeted tissues and maximize local concentration of the drug, or delivered through the bloodstream (intravenous) or gastrointestinal system (oral) to simplify administration. Once delivered to the tissue of interest, the vehicle–siRNA complexes must reach the target cells and cross the plasma membrane to enter the cytoplasm. At this point, the siRNA must be released from the vehicle in order to be recognized by the RNAi machinery.