Ewert Kai K, Zidovska Alexandra, Ahmad Ayesha, Bouxsein Nathan F, Evans Heather M, McAllister Christopher S, Samuel Charles E, Safinya Cyrus R
Physics, Materials & Molecular, Cellular and Developmental Biology Department, University of California at Santa Barbara, Santa Barbara, CA 93106, USA.
Top Curr Chem. 2010;296:191-226. doi: 10.1007/128_2010_70.
Motivated by the promises of gene therapy, there is great interest in developing non-viral lipid-based vectors for therapeutic applications due to their low immunogenicity, low toxicity, ease of production, and the potential of transferring large pieces of DNA into cells. In fact, cationic liposome (CL) based vectors are among the prevalent synthetic carriers of nucleic acids (NAs) currently used in gene therapy clinical trials worldwide. These vectors are studied both for gene delivery with CL-DNA complexes and gene silencing with CL-siRNA (short interfering RNA) complexes. However, their transfection efficiencies and silencing efficiencies remain low compared to those of engineered viral vectors. This reflects the currently poor understanding of transfection-related mechanisms at the molecular and self-assembled levels, including a lack of knowledge about interactions between membranes and double stranded NAs and between CL-NA complexes and cellular components. In this review we describe our recent efforts to improve the mechanistic understanding of transfection by CL-NA complexes, which will help to design optimal lipid-based carriers of DNA and siRNA for therapeutic gene delivery and gene silencing.
受基因治疗前景的推动，人们对开发用于治疗应用的非病毒脂质载体有着浓厚兴趣，因为它们具有低免疫原性、低毒性、易于生产以及将大片段DNA导入细胞的潜力。事实上，基于阳离子脂质体（CL）的载体是目前全球基因治疗临床试验中普遍使用的核酸（NA）合成载体之一。这些载体既用于CL-DNA复合物的基因递送，也用于CL-siRNA（小干扰RNA）复合物的基因沉默研究。然而，与工程化病毒载体相比，它们的转染效率和沉默效率仍然较低。这反映出目前在分子和自组装水平上对转染相关机制的理解不足，包括对膜与双链NA之间以及CL-NA复合物与细胞成分之间相互作用的了解匮乏。在这篇综述中，我们描述了我们最近为增进对CL-NA复合物转染机制理解所做的努力，这将有助于设计用于治疗性基因递送和基因沉默的最佳DNA和siRNA脂质载体。
