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

May 22, 2024Journal of the American Chemical Society

Making imidazole-based ionizable lipids to deliver messenger RNA efficiently and selectively to the spleen

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Abstract

A3B7C2-based lipid nanoparticles achieved a remarkable 98% proportion of splenic transfection in mRNA delivery.

Imidazole-containing ionizable lipids (IMILs) show a strong preference for delivering mRNA to the spleen.
A3B7C2 was identified as a top-performing IMIL for spleen-specific mRNA delivery after screening a multidimensional library.
A3B7C2-based lipid nanoparticles demonstrated a 2.8-fold and 12.9-fold increase in mRNA transfection efficiency compared to other lipid formulations.
This approach resulted in an 18.3-fold enhancement in splenic mRNA expression compared to a previous method without additional anionic lipids.
The findings suggest potential for improved mRNA therapeutics targeting spleen-related conditions.

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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-throughputscreening, 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. in vivo

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

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