Discovery of Ketal‐Ester Ionizable Lipid Nanoparticle with Reduced Hepatotoxicity, Enhanced Spleen Tropism for mRNA Vaccine Delivery

Oct 10, 2024Advanced science (Weinheim, Baden-Wurttemberg, Germany)

New Ionizable Lipid Nanoparticle That Is Less Toxic to the Liver and Targets the Spleen Better for mRNA Vaccine Delivery

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Abstract

(4S)-KEL12 LNP demonstrated significantly higher delivery efficacy and lower toxicity than the DLin-MC3-DMA LNP.

(4S)-KEL12 is identified as a safe and efficient lipid for delivering mRNA.
This lipid showed better spleen targeting and reduced liver toxicity compared to SM-102 LNP.
(4S)-KEL12 displayed good biodegradability after being injected either intramuscularly or intravenously.
When used with a therapeutic mRNA cancer vaccine, (4S)-KEL12 elicited strong immune responses and substantial tumor regression in mice.
The findings provide insights into the structure-activity relationship and performance of lipid nanoparticle delivery systems.

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The safety and efficacy of the lipid nanoparticle (LNP) delivery system are crucial for the successful development of messenger RNA vaccines. We designed and synthesized a series of ketal ester lipids (KELs), featuring a biodegradable ketal moiety in the linker and ester segments in the tail. Through iterative optimization of the head and tail groups of KELs, we tuned the pKa and molecular shapes, and identified (4S)-KEL12 as a safe and efficient ionizable lipid for mRNA delivery. (4S)-KEL12 LNP showed significantly higher delivery efficacy and lower toxicity than the DLin-MC3-DMA LNP. In comparison to SM-102 LNP, (4S)-KEL12 LNP exhibited better spleen tropism, reduced liver tropism, and hepatotoxicity. Additionally, (4S)-KEL12 demonstrated good biodegradability following intramuscular or intravenous injection. Notably, (4S)-KEL12 LNP encapsulated with a therapeutic mRNA cancer vaccine elicited robust cellular immune responses leading to substantial tumor regression along with prolonged survival in tumor-bearing mice. Our results suggest that (4S)-KEL12 LNP holds great promise for mRNA vaccine delivery. The comprehensive analysis of the structure-activity relationship, toxicity, biodegradability, distribution, expression, efficacy, and stereochemistry of these LNPs will greatly contribute to the rational design and discovery of novel lipid-based delivery systems.

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Discovery of Ketal‐Ester Ionizable Lipid Nanoparticle with Reduced Hepatotoxicity, Enhanced Spleen Tropism for mRNA Vaccine Delivery

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