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-1 to achieve a 107 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.

中文翻译：

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用于将 mRNA 递送至肝脏的脂质修饰氨基糖苷类。

阳离子脂质纳米颗粒（LNP）广泛用作核酸递送的载体。大多数阳离子脂质的合成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，其在结构和功能上对于开发用于核酸递送的新载体都很有意义。在此，阳离子脂质修饰氨基糖苷类 (CLA) 被探索作为信使 RNA (mRNA) 递送的载体家族。CLA 是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的。热门产品 (GT-EP10) 能够以 0.05 mg kg-1 的剂量将 Luc mRNA 递送至 C57BL/6 小鼠，在肝脏中实现 107 的平均发光强度。Lox-Stop-Lox tdTomato 小鼠模型用于进一步证明这种高效的 mRNA 递送系统可用于基因编辑。人类促红细胞生成素 mRNA 的成功递送表明，基于 CLA 的 LNP 在未来递送治疗性核酸方面具有广阔的前景。