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Multicomponent Synthesis of Imidazole-Based Ionizable Lipids for Highly Efficient and Spleen-Selective Messenger RNA Delivery.
Dong, Wang; Li, Zhibin; Hou, Tailin; Shen, Yanqiong; Guo, Zixuan; Su, Yi-Tan; Chen, Ziqi; Pan, Huimin; Jiang, Wei; Wang, Yucai.
Affiliation
  • Dong W; 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.
  • Li Z; 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.
  • Hou T; 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.
  • Shen Y; Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230601, China.
  • Guo Z; 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.
  • Su YT; Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230601, China.
  • Chen Z; 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.
  • Pan H; 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.
  • Jiang W; 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.
  • Wang Y; 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.
J Am Chem Soc ; 146(22): 15085-15095, 2024 Jun 05.
Article in En | MEDLINE | ID: mdl-38776232
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Spleen / RNA, Messenger / Imidazoles / Lipids Limits: Animals Language: En Journal: J Am Chem Soc / Journal of the american chemical society / J. am. chem. soc Year: 2024 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Spleen / RNA, Messenger / Imidazoles / Lipids Limits: Animals Language: En Journal: J Am Chem Soc / Journal of the american chemical society / J. am. chem. soc Year: 2024 Document type: Article Affiliation country: Country of publication: