Multicomponent Synthesis of Imidazole-Based Ionizable Lipids for Highly Efficient and Spleen-Selective Messenger RNA Delivery

IF 14.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Journal of the American Chemical Society Pub Date : 2024-05-22 DOI:10.1021/jacs.4c00451
Wang Dong, Zhibin Li, Tailin Hou, Yanqiong Shen, Zixuan Guo, Yi-Tan Su, Ziqi Chen, Huimin Pan, Wei Jiang* and Yucai Wang*, 
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Abstract

The spleen emerges as a pivotal target for mRNA delivery, prompting a continual quest for specialized and efficient lipid nanoparticles (LNPs) designed to enhance spleen-selective transfection efficiency. Here we report imidazole-containing ionizable lipids (IMILs) that demonstrate a pronounced preference for mRNA delivery into the spleen with exceptional transfection efficiency. We optimized IMIL structures by constructing and screening a multidimensional IMIL library containing multiple heads, tails, and linkers to perform a structure–activity correlation analysis. Following high-throughput in vivo screening, we identified A3B7C2 as a top-performing IMIL in spleen-specific mRNA delivery via the formulated LNPs, achieving a remarkable 98% proportion of splenic transfection. Moreover, A3B7C2-based LNPs are particularly potent in splenic dendritic cell transfection. Comparative analyses revealed that A3B7C2-based LNPs achieved a notable 2.8-fold and 12.9-fold increase in splenic mRNA transfection compared to SM102 and DLin-MC3-DMA lipid formulations, respectively. Additionally, our approach yielded an 18.3-fold enhancement in splenic mRNA expression compared to the SORT method without introducing additional anionic lipids. Collectively, these IMILs highlight promising avenues for further research in spleen-selective mRNA delivery. This work offers valuable insights for the swift discovery and rational design of ionizable lipid candidates tailored for spleen-selective transfection, thereby facilitating the application of mRNA therapeutics in spleen-related interventions.

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多组分合成基于咪唑的可离子化脂质,用于高效和脾选择性传递信使 RNA。
脾脏是 mRNA 运送的关键靶点,这促使人们不断探索专门设计的高效脂质纳米颗粒 (LNP),以提高脾脏选择性转染效率。在此,我们报告了含咪唑的可电离脂质(IMILs),它们在向脾脏递送 mRNA 时表现出明显的偏好,并具有卓越的转染效率。我们通过构建和筛选包含多个头部、尾部和连接体的多维 IMIL 库,优化了 IMIL 结构,并进行了结构-活性相关性分析。经过高通量体内筛选,我们发现 A3B7C2 是通过配制的 LNPs 传递脾脏特异性 mRNA 性能最好的 IMIL,其脾脏转染率高达 98%。此外,基于 A3B7C2 的 LNPs 在脾脏树突状细胞转染中效果尤为显著。比较分析表明,与 SM102 和 DLin-MC3-DMA 脂质制剂相比,基于 A3B7C2 的 LNPs 的脾脏 mRNA 转染率分别显著提高了 2.8 倍和 12.9 倍。此外,与 SORT 方法相比,我们的方法在不引入额外阴离子脂质的情况下,使脾脏 mRNA 表达提高了 18.3 倍。总之,这些 IMILs 为进一步研究脾脏选择性 mRNA 递送开辟了前景广阔的途径。这项工作为迅速发现和合理设计适合脾脏选择性转染的可离子化脂质候选物提供了宝贵的见解,从而促进了 mRNA 疗法在脾脏相关干预中的应用。
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来源期刊
CiteScore
24.40
自引率
6.00%
发文量
2398
审稿时长
1.6 months
期刊介绍: The flagship journal of the American Chemical Society, known as the Journal of the American Chemical Society (JACS), has been a prestigious publication since its establishment in 1879. It holds a preeminent position in the field of chemistry and related interdisciplinary sciences. JACS is committed to disseminating cutting-edge research papers, covering a wide range of topics, and encompasses approximately 19,000 pages of Articles, Communications, and Perspectives annually. With a weekly publication frequency, JACS plays a vital role in advancing the field of chemistry by providing essential research.
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