Yu Xueliang, Liu Shuai, Cheng Qiang, Wei Tuo, Lee Sang, Zhang Di, Siegwart Daniel J
Department of Biochemistry, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Adv Healthc Mater. 2020 Apr;9(7):e1901487. doi: 10.1002/adhm.201901487. Epub 2020 Feb 28.
Cationic lipid nanoparticles (LNPs) are widely used as carriers for delivery of nucleic acids. Most synthetic routes toward cationic lipids have derived from simple amine cores. Greater chemical diversity can be obtained through starting with natural products containing basic nitrogen atoms, which offers routes to more complex molecules. Natural building blocks are not extensively explored, such as aminoglycosides, which are both structurally and functionally interesting for developing new carriers for nucleic acid delivery. Herein, cationic lipid-modified aminoglycosides (CLAs) are explored as a family of vehicles for messenger RNA (mRNA) delivery. CLAs are synthesized from natural existing aminoglycosides coupling with alkyl epoxides and acrylates. The top hit (GT-EP10) is able to deliver Luc mRNA to C57BL/6 mice at a dose of 0.05 mg kg to achieve a 10 average luminescence intensity in the liver. The Lox-Stop-Lox tdTomato mouse model is used to further demonstrate that this efficient mRNA delivery system can be potentially used for gene editing. Successful delivery of human erythropoietin mRNA shows that CLA-based LNPs have promising opportunities for delivery of therapeutic nucleic acids in the future.
阳离子脂质纳米颗粒（LNPs）被广泛用作核酸递送载体。大多数合成阳离子脂质的路线都源自简单的胺核心。从含有碱性氮原子的天然产物开始可以获得更大的化学多样性，这为合成更复杂的分子提供了途径。天然构建模块尚未得到广泛探索，例如氨基糖苷类，其在开发新型核酸递送载体方面在结构和功能上都很有趣。在此，阳离子脂质修饰的氨基糖苷类（CLAs）被探索作为一类用于信使核糖核酸（mRNA）递送的载体。CLAs由天然存在的氨基糖苷类与烷基环氧化物和丙烯酸酯偶联合成。最佳的（GT-EP10）能够以0.05毫克/千克的剂量将荧光素酶mRNA递送至C57BL/6小鼠，在肝脏中实现平均发光强度为10。Lox-Stop-Lox tdTomato小鼠模型用于进一步证明这种高效的mRNA递送系统可潜在地用于基因编辑。成功递送人促红细胞生成素mRNA表明基于CLA的LNPs在未来递送治疗性核酸方面具有广阔前景。
