A Multidimensional Approach to Modulating Ionizable Lipids for High‐Performing and Organ‐Selective mRNA Delivery

Sep 3, 2023Angewandte Chemie (International ed. in English)

Controlling Ionizable Lipids to Improve mRNA Delivery and Target Specific Organs

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Abstract

A large library of new ionizable lipids (ILs) was established, enhancing the delivery of mRNA via lipid nanoparticles (LNPs).

The Ugi four-component reaction (Ugi-4CR) was utilized to efficiently create diverse IL structures under mild conditions.
Top-performing ILs were identified for improved organ-specific delivery of mRNA from the liver to the spleen.
The performance of LNPs for mRNA delivery was significantly influenced by the isomeric forms of the ILs used.
The formation of bis-amide bonds in the Ugi-4CR may promote hydrogen bonding between ILs, aiding in the stabilization of LNPs.
This work may assist in the rapid discovery and design of IL candidates for mRNA therapeutics.

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The development of lipid nanoparticles (LNPs) has enabled a successful clinical application of mRNA vaccines. However, disclosure of design principles for the core component-ionizable lipids (ILs), improving the delivery efficacy and organ targeting of LNPs, remains a formidable challenge. Herein, we report a powerful strategy to modulate ILs in one-step chemistry using the Ugi four-component reaction (Ugi-4CR) under mild conditions. A large IL library of new structures was established simply and efficiently through a multidimensional approach, allowing us to identify the top-performing ILs in delivering mRNA via the formulated LNPs. Adjusting the skeleton of ILs has transformed the organ-specific and robust transfection in mRNA delivery from the liver to the spleen following different administration routes. Of note, a series of isomeric ILs were prepared and we found that the isomers mattered greatly in the performance of LNPs for mRNA delivery. Furthermore, owing to the bis-amide bonds formed in the Ugi-4CR reaction, the ILs within LNPs may form hydrogen bonding intermolecularly, facilitating the colloidal stabilization of LNPs. This work provides clues to the rapid discovery and rational design of IL candidates, assisting the application of mRNA therapeutics.

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A Multidimensional Approach to Modulating Ionizable Lipids for High‐Performing and Organ‐Selective mRNA Delivery

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