Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Curr Top Med Chem. 2012;12(2):97-107. doi: 10.2174/156802612798919141.
A key hurdle for the further development of RNA interference (RNAi) therapeutics like small interfering RNA (siRNA) is their safe and effective delivery. Lipids are promising and versatile carriers because they are based on Nature's own building blocks and can be provided with properties which allow for protection of the siRNA, steric stabilization, targeting, membrane fusion and triggered drug release. At present a variety of lipid-based transfectants for siRNA delivery have been used for in vitro and in vivo purposes. The majority bears a cationic charge to electrostatically complex the siRNA into more hydrophobic lipoplexes, which promote passage of the siRNA across cellular membrane barriers, especially when lipids are added that facilitate membrane fusion. Despite these attractive features, siRNA delivery vehicles are facing a number of challenges such as the limited delivery efficiency in vivo, toxicity and non-specific stimulation of the immune system. To optimally design and tailor the lipidic systems for siRNA delivery, better insight is needed into the mechanisms of cell delivery. More specifically, further clarification is need regarding the nature of cell surface interactions, routes of internalization, passage of intracellular membranes, and mechanisms of immune activation. This review provides an overview of the main constituents currently employed in lipid-based siRNA carriers, and recent research into improvements of cell delivery. In addition, pitfalls related to immune activation and side effects are discussed, and possible ways to overcome them are highlighted.
RNA 干扰 (RNAi) 治疗药物（如小干扰 RNA (siRNA)）进一步发展的一个关键障碍是其安全有效的递送。脂质是一种很有前途且多功能的载体，因为它们基于自然界自身的构建块，并可以赋予其保护 siRNA、立体稳定、靶向、膜融合和触发药物释放的特性。目前，已经有多种基于脂质的转染试剂用于 siRNA 的体外和体内递送。大多数转染试剂带有正电荷，以静电方式将 siRNA 复合成更疏水的脂质体，从而促进 siRNA 穿过细胞膜屏障，尤其是添加了促进膜融合的脂质时。尽管具有这些吸引人的特性，但 siRNA 递药载体仍面临一些挑战，例如体内递送效率有限、毒性和非特异性刺激免疫系统。为了优化设计和定制用于 siRNA 递送的脂质系统，需要更好地了解细胞递药的机制。更具体地说，需要进一步阐明细胞表面相互作用的性质、内化途径、细胞内膜的通过以及免疫激活的机制。本文综述了目前用于基于脂质的 siRNA 载体的主要成分，并介绍了最近关于改善细胞递药的研究。此外，还讨论了与免疫激活和副作用相关的陷阱，并强调了可能的克服方法。
