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Ionizable Lipids from Click Reactions for Lipid Nanoparticle Assembling and mRNA Delivery.
Journal of Physical Chemistry. B 2024 April 9
Ionizable lipid-containing lipid nanoparticles (LNPs) are regarded as promising nonviral vectors for gene therapy delivery systems. Rationale design of the ionizable lipid structure based on initial screening of ionizable lipid molecule libraries combined with systematic comparison and analysis on the physical chemical parameters related to delivery efficiency greatly accelerated the discovery of novel LNP candidates for delivering various nucleic acid therapeutics like mRNAs (mRNAs). Based on the copper-catalyzed azide-alkyne click reaction, which is highly efficient and biocompatible, we were able to obtain the lipid molecule library containing a common triazole moiety between different lipid tails and various substituents as hydrophilic head groups. Herein, we systematically investigated the change of p K a values of different ionizable lipid molecules with different substituents as head groups in the click-based lipid library, mapping the p K a value change to different steps in the process of the LNP assembly and mRNA delivery. Systematic analyses on the data including the p K a value of the ionized lipids and the encapsulation and delivery efficiency of mRNA in LNPs with these ionized lipids provided the possibility of rational design on the head and tail structure for the triazole containing ionized lipids to realize highly efficient delivery of different mRNAs.
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