Increasing the siRNA knockdown efficiency of lipid nanoparticles by morphological transformation with the use of dihydrosphingomyelin as a helper lipid
Increasing the siRNA knockdown efficiency of lipid nanoparticles by morphological transformation with the use of dihydrosphingomyelin as a helper lipid
复制标题
使用二氢鞘磷脂作为辅助脂质通过形态转化提高脂质纳米颗粒的 siRNA 敲除效率
DOI：
10.1039/d3bm00068k
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发表时间：
2023
影响因子：
6.6
通讯作者：
Asai Tomohiro
中科院分区：
文献类型：
--
作者：
Hashimoto Masahiro;Yonezawa Sei;Furan Song;Nitta Chiori;Maeda Noriyuki;Tomita Koji;Yokouchi Ayano;Koide Hiroyuki;Asai Tomohiro
脂质纳米颗粒（LNP），包括可电离脂质、辅助脂质、胆固醇和PEG脂质，可以充当核酸的递送载体，并且已经在siRNA和mRNA的递送中取得了临床成功。已经表明，LNP的形态根据其脂质组成而变化，但其形态对核酸功效的影响尚未完全阐明。在这项研究中，我们使用我们以前开发的新型脂质，二油酰甘油磷酸-二乙二胺缀合物（DOP-DEDA），以创建pH响应LNP（DOP-DEDA LNP）。我们评估了由不同辅助脂质组成的DOP-DEDA LNP的形态和小干扰RNA（siRNA）的敲低效率。在不同辅助脂质的DOP-DEDA LNP之间观察到形态上的显著差异。在DOP-DEDA LNP的表观pKa和siRNA的敲低效率中也观察到显著差异，这可能是由于DOP-DEDA分子在DOP-DEDA LNP中定位的差异。这些发现表明，改变辅助脂质改变了DOP-DEDA LNP系统的形态，这影响了siRNA的表观pKa和敲低效率。
Lipid nanoparticles (LNPs), comprising ionizable lipids, helper lipids, cholesterol, and PEG lipids, can act as delivery carriers for nucleic acids and have achieved clinical success in the delivery of siRNA and mRNA. It has been shown that the morphology of LNPs varies depending on their lipid composition, but the influence of their morphology on nucleic acid efficacy has not been fully elucidated. In this study, we used our previously developed novel lipid, dioleoylglycerophosphate-diethylenediamine conjugate (DOP-DEDA), to create pH-responsive LNPs (DOP-DEDA LNPs). We evaluated the morphology of DOP-DEDA LNPs composed of different helper lipids and the knockdown efficiency of small interfering RNA (siRNA). A distinctive difference in morphology was observed between DOP-DEDA LNPs of different helper lipids. Significant differences were also observed in the apparent pKa of DOP-DEDA LNPs and the knockdown efficiency of siRNA, which may be due to the difference in the localization of DOP-DEDA molecules in DOP-DEDA LNPs. These findings suggest that changing helper lipids alters the morphology of the DOP-DEDA LNP system, which affects the apparent pKa and knockdown efficiency of siRNA.