Department of Radiology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230601, China.
J Am Chem Soc. 2024 Jun 5;146(22):15085-15095. doi: 10.1021/jacs.4c00451. Epub 2024 May 22.
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 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.
脾脏作为 mRNA 递送的关键靶标出现，促使人们不断寻求专门且高效的脂质纳米颗粒 (LNP)，以提高脾脏选择性转染效率。在这里，我们报告了含有咪唑的可离子化脂质 (IMIL)，它们对 mRNA 向脾脏的递送表现出明显的偏好，具有出色的转染效率。我们通过构建和筛选包含多个头部、尾部和连接子的多维 IMIL 文库，对 IMIL 结构进行了优化，以进行构效关系分析。经过高通量筛选，我们确定了 A3B7C2 是一种通过配方 LNP 进行脾脏特异性 mRNA 递送的顶级 IMIL，通过 LNP 实现了高达 98%的脾脏转染比例。此外，A3B7C2 基 LNP 特别擅长脾脏树突状细胞的转染。比较分析表明，与 SM102 和 DLin-MC3-DMA 脂质配方相比，基于 A3B7C2 的 LNP 分别使脾脏 mRNA 转染提高了 2.8 倍和 12.9 倍。此外，与不引入额外阴离子脂质的 SORT 方法相比，我们的方法使脾脏 mRNA 表达提高了 18.3 倍。总之，这些 IMIL 为脾脏选择性 mRNA 递送的进一步研究提供了有前途的途径。这项工作为快速发现和合理设计针对脾脏选择性转染的可离子化脂质候选物提供了有价值的见解，从而促进了 mRNA 疗法在脾脏相关干预中的应用。
