Development of Sulfonium- and Phosphonium-based Cationic Lipid Materials for mRNA Delivery

总结 基于mRNA的治疗剂在疾病预防中具有广泛的应用， 治疗然而，其广泛的实际应用在很大程度上受到递送的限制。 性问题阳离子脂质是mRNA递送的有效载体材料， 脂质分子的化学结构在确定递送功效方面是关键的。 然而，目前还没有广泛接受的指导原则存在合理的脂质 分子结构设计，以实现假定的生物学效应。的整合 组合化学和体外/体内筛选方法已被证明 可用于开发有效的脂质载体。在综合方面投入了巨大的努力 具有新化学结构的新脂质。然而，尽管取得了可喜的成果， 几乎所有目前开发的用于mRNA递送的阳离子脂质都含有初级， 仲、叔或季铵化氨基作为可带电单元与 货物mRNA。在本研究中，我们提出开发两种新型阳离子脂质 具有含锍和磷的头部和可生物降解的尾部的分子 并探讨其在体外mRNA传递中的应用。我们的假设是 相对于传统的基于胺的阳离子脂质，基于锍和膦的脂质 将具有前所未有的自组装行为，mRNA递送性能，细胞 靶向和生物相容性特征。通过使用组合文库合成策略， 在体外筛选方法，并制定优化方法，本项目是第一个 开发可生物降解的锍和磷基脂质，并探索其 细胞内mRNA递送的可行性和安全性。开发的新脂质材料 也可用于未来的研究以递送其他类型的治疗剂， 例如小分子药物、蛋白质和基因。

SUMMARY The mRNA-based therapeutics has wide applications in disease prevention and treatment. However, its wide practical application is largely limited by the delivery concerns. Cationic lipids are effective carrier materials for mRNA delivery and the chemical structure of lipid molecules is critical in determining the delivery efficacy. However, currently, there are no wide-accepted guiding principles exist for rational lipid molecule structure design to achieve presumed biological effects. The integration of combinatorial chemistry and in vitro/in vivo screening approach has been demonstrated useful in developing effective lipid carriers. Great efforts have been put into the synthesis of new lipids with novel chemical structures. However, despite all the promising results, almost all currently developed cationic lipids for mRNA delivery contain primary, secondary, tertiary, or quaternized amino groups as the chargeable units to interact with the cargo mRNAs. In this study, we propose to develop two new types of cationic lipid molecules with sulfonium- and phosphonium-containing heads and biodegradable tails and explore their applications in in vitro mRNA delivery. Our hypothesis is that contrary to traditional amine-based cationic lipids, the sulfonium- and phosphonium-based lipids will have unprecedented self-assembly behaviors, mRNA delivery performances, cell targeting, and biocompatibility profiles. By using combinatorial library synthesis strategy, in vitro screening approach, and formulation optimization methods, this project is the first to develop biodegradable sulfonium- and phosphonium-based lipids and to explore their feasibility and safety for intracellular mRNA delivery. The new lipid materials developed in this study can also be used in future studies to deliver other types of therapeutics, such as small molecule drugs, proteins, and genes.