Huo Haonan, Cheng Xingdi, Xu Jiaxi, Lin Jiaqi, Chen Ning, Lu Xueguang
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
J Mater Chem B. 2023 May 17;11(19):4171-4180. doi: 10.1039/d3tb00516j.
The efficacy of messenger RNA (mRNA)-based vaccines or therapies relies on delivery vehicles that can transport them into the cytosol of cells. Lipid nanoparticles (LNPs) are the most clinically advanced carrier for mRNA. The chemical structure of an ionizable lipid is critical for the delivery efficiency of the LNPs. Herein, we synthesize a new ionizable lipid containing fluorinated alkyl chains (F-L319) and evaluate its mRNA delivery efficiency compared to its hydrocarbon counterpart (L319). While LNPs formulated with F-L319 alone showed decreased mRNA encapsulation and delivery efficiencies in comparison to the L319-LNP, we found that combining the appropriate ratios of F-L319 and L319 as hybrid ionizable lipids in LNPs (hybrid-LNPs) greatly enhanced mRNA delivery efficiency both and . Upon intravenous injection, the hybrid-LNP showed targeted mRNA expression in the spleen. Mechanistic studies indicate that the enhanced mRNA delivery of the hybrid-LNP is attributed to both improved mRNA encapsulation and cellular uptake. Collectively, fluorination of ionizable lipids represents a promising strategy to improve the delivery efficiency of LNPs.
基于信使核糖核酸（mRNA）的疫苗或疗法的疗效依赖于能够将它们转运到细胞胞质溶胶中的递送载体。脂质纳米颗粒（LNPs）是用于mRNA的临床上最先进的载体。可电离脂质的化学结构对于LNPs的递送效率至关重要。在此，我们合成了一种含有氟化烷基链的新型可电离脂质（F-L319），并将其与含烃对应物（L319）相比评估其mRNA递送效率。虽然单独用F-L319配制的LNPs与L319-LNP相比显示出降低的mRNA包封率和递送效率，但我们发现，在LNPs中将适当比例的F-L319和L319作为混合可电离脂质组合（混合-LNPs）极大地提高了mRNA递送效率。静脉注射后，混合-LNP在脾脏中显示出靶向mRNA表达。机制研究表明，混合-LNP增强的mRNA递送归因于改善的mRNA包封和细胞摄取。总体而言，可电离脂质的氟化是提高LNPs递送效率的一种有前景的策略。
