Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB, Canada.
Biomaterials. 2012 Mar;33(8):2546-69. doi: 10.1016/j.biomaterials.2011.11.079. Epub 2011 Dec 30.
The discovery of RNA interference (RNAi) has excited the scientific field due to its potential for wide range of therapeutic applications. The pharmacological mediator of RNAi, short interfering RNA (siRNA), however, has faced significant obstacles in reaching its target site and effectively exerting its silencing activity. Effective pharmacological use of siRNA requires 'carriers' that can deliver the siRNA to its intended site of action. The carriers assemble the siRNA into supramolecular complexes that display functional properties during the delivery process. This review will summarize non-viral approaches to siRNA delivery, emphasizing the current obstacles to delivery and the mechanisms employed to overcome these obstacles. The carriers successfully pursued in pre-clinical (animal) models will be presented so as to provide a glimpse of possible candidates for clinical testing. Supramolecular assembly of nucleic acids with carriers will be probed from thermodynamics and computational perspectives to understand supramolecular structures and their dynamics. The delivery and trafficking requirements for siRNA are then dissected and engineering approaches to overcoming these barriers will be articulated. The latter has been attempted both at the cellular levels, focusing on intracellular barriers, as well as systemic level, emphasizing macroscopic challenges affecting siRNA delivery. Clinical experience with non-viral siRNA delivery is summarized, highlighting the nature delivery modes attempted in clinical settings. We conclude with a perspective on the future of siRNA therapeutics, specifically concentrating on the possible impact of non-viral carriers in the field.
RNA 干扰 (RNAi) 的发现因其广泛的治疗应用潜力而激发了科学界的兴趣。然而，RNAi 的药理学介导物，即短干扰 RNA (siRNA)，在到达其靶位并有效发挥其沉默活性方面面临着重大障碍。siRNA 的有效药理学应用需要“载体”，可以将 siRNA 递送到其预期的作用部位。载体将 siRNA 组装成超分子复合物，在递药过程中显示出功能特性。这篇综述将总结 siRNA 递送的非病毒方法，重点介绍递送的当前障碍和克服这些障碍所采用的机制。将介绍在临床前（动物）模型中成功探索的载体，以期为临床测试提供可能的候选物。将从热力学和计算角度探讨核酸与载体的超分子组装，以了解超分子结构及其动力学。然后将剖析 siRNA 的递送和转运要求，并阐述克服这些障碍的工程方法。后者不仅在细胞水平上针对细胞内障碍进行了尝试，而且还在系统水平上针对影响 siRNA 递送的宏观挑战进行了尝试。总结了非病毒 siRNA 递送的临床经验，重点介绍了临床环境中尝试的递送模式。我们以 siRNA 治疗学的未来展望作为结论，特别是集中讨论非病毒载体在该领域的可能影响。
