Synergistic Silencing: Combinations of Lipid-like Materials for Efficacious siRNA Delivery
Synergistic Silencing: Combinations of Lipid-like Materials for Efficacious siRNA Delivery
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DOI：
10.1038/mt.2011.141
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发表时间：
2011-09-01
影响因子：
12.4
通讯作者：
Anderson, Daniel G.
中科院分区：
文献类型：
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作者：
Whitehead, Kathryn A.;Sahay, Gaurav;Anderson, Daniel G.
尽管RNA干扰（RNAi）疗法前景光明，但由于将短干扰RNA （siRNA）递送到体内细胞靶点的困难，临床进展缓慢。迄今为止开发的几乎所有siRNA运载工具都使用单一阳离子或电离材料。为了增加可用于siRNA递送疗法开发的材料空间，本研究考察了使用可电离脂质样材料的二元组合来协同实现基因沉默的可能性。有趣的是，研究人员发现，无效的单一类脂物质可以在单一递送载体中一起形成，分别诱导HeLa细胞和小鼠中萤火虫荧光素酶和因子VII的几乎完全敲除。显微镜实验表明，当结合分别介导细胞摄取和内体逃逸的物质时，产生协同作用，这是递送过程中的两个重要步骤。总之，这些数据表明，联合制备类脂质材料可以显著改善siRNA的递送结果，同时增加治疗开发的材料空间。预计这种二元配方策略可适用于利用两步内体传递途径的任何靶细胞群中的任何siRNA传递材料。
Despite the promise of RNA interference (RNAi) therapeutics, progress toward the clinic has been slowed by the difficulty of delivering short interfering RNA (siRNA) into cellular targets within the body. Nearly all siRNA delivery vehicles developed to date employ a single cationic or ionizable material. In order to increase the material space available for development of siRNA delivery therapeutics, this study examined the possibility of using binary combinations of ionizable lipid-like materials to synergistically achieve gene silencing. Interestingly, it was found that ineffective single lipid-like materials could be formulated together in a single delivery vehicle to induce near-complete knockdown of firefly luciferase and factor VII in HeLa cells and in mice, respectively. Microscopy experiments suggested that synergistic action resulted when combining materials that respectively mediated cellular uptake and endosomal escape, two important steps in the delivery process. Together, the data indicate that formulating lipid-like materials in combination can significantly improve siRNA delivery outcomes while increasing the material space available for therapeutic development. It is anticipated that this binary formulation strategy could be applicable to any siRNA delivery material in any target cell population that utilizes the two-step endosomal delivery pathway.