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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Self-assembled lamellar complexes of siRNA with lipidic aminoglycoside derivatives promote efficient siRNA delivery and interference
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Self-assembled lamellar complexes of siRNA with lipidic aminoglycoside derivatives promote efficient siRNA delivery and interference

机译：siRNA与脂质氨基糖苷衍生物的自组装层状复合物可促进有效的siRNA传递和干扰

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摘要

RNA interference requires efficient delivery of small double-stranded RNA molecules into the target cells and their subsequent incorporation into RNA-induced silencing complexes. Although current cationic lipids commonly used for DNA transfection have also been used for siRNA transfection, a clear need still exists for better siRNA delivery to improve the gene silencing efficiency. We synthesized a series of cationic lipids characterized by head groups bearing various aminoglycosides for specific interaction with RNA. siRNA complexation with such lipidic aminoglycoside derivatives exhibited three lipid/siRNA ratio-dependent domains of colloidal stability. Fluorescence and dynamic light-scattering experiments showed that cationic lipid/siRNA complexes were formed at lower charge ratios, exhibited a reduced zone of colloidal instability, and had smaller mean diameters compared with our previously described guanidinium-based cationic lipids. Cryo-transmission electron microscopy and x-ray-scattering experiments showed that, although the final in toto morphology of the lipid/siRNA complexes depended on the aminoglycoside type, there was a general su-pramolecular arrangement consisting of ordered lamellar domains with an even spacing of 67 A. The most active cationic lipid/siRNA complexes for gene silencing were obtained with 4,5-disubstituted 2-deoxystreptamine aminoglycoside derivatives and were characterized by the siRNA being entrapped in small particles exhibiting lamellar microdomains corresponding to siRNA molecules sandwiched between the lipid bilayers. These results clearly show that lipidic aminoglycoside derivatives constitute a versatile class of siRNA nanocarriers allowing efficient gene silencing.
机译：RNA干扰需要将小的双链RNA分子有效递送到靶细胞中，然后将其随后掺入RNA诱导的沉默复合物中。尽管目前通常用于DNA转染的阳离子脂质也已用于siRNA转染，但仍然明显需要更好的siRNA传递以提高基因沉默效率。我们合成了一系列阳离子脂质，其特征是带有各种氨基糖苷的头基与RNA发生特异性相互作用。与此类脂质氨基糖苷衍生物的siRNA络合显示出胶体稳定性的三个脂质/ siRNA比依赖性结构域。荧光和动态光散射实验表明，与我们先前所述的基于胍基的阳离子脂质相比，阳离子脂质/ siRNA复合物在较低的电荷比下形成，显示出胶体不稳定性降低的区域，并且平均直径更小。低温透射电镜和X射线散射实验表明，尽管脂质/ siRNA复合物的最终内在形态取决于氨基糖苷类型，但仍存在由有序层状结构域和均匀间隔组成的一般超分子排列67 A.用于基因沉默的活性最高的阳离子脂质/ siRNA复合物是用4,5-二取代的2-脱氧链胺基氨基糖苷衍生物获得的，其特征是siRNA被包裹在小颗粒中，显示出层状微区，对应于夹在脂质之间的siRNA分子。双层。这些结果清楚地表明，脂质氨基糖苷衍生物构成一类通用的siRNA纳米载体，可实现有效的基因沉默。

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