Ionizable lipids are a class of lipid molecules which remain neutral at physiological pH, but are protonated at low pH, making them positively charged, ALC-0315 (Figure 1) is an example with the amine site that can be protonated at low pH.
Figure 1: Structure of ALC-0315
Ionizable lipids are one key component of Ionizable lipid nanoparticles (LNPs) which have been widely used for the systemic delivery of RNA therapeutics. Other lipid molecules in LNPs include helper lipid, cholesterol, and PEG lipid, etc.
Commonly reported ionizable lipid materials were reported for LNP formulations include C12-200, cKK-E12, and DLin-MC3-DMA). These LNPs showed an efficient gene silencing in the liver at the dosing level of 0.002 mg of siRNA/kg.
The pH-sensitivity of ionizable lipids is beneficial for mRNA delivery in vivo, because neutral lipids have less interactions with the anionic membranes of blood cells which improves the biocompatibility of lipid nanoparticles. Trapped in endosomes, in which the pH is lower than the pH in the extracellular environment, ionizable lipids are protonated and become positively charged, which may promote membrane destabilization and facilitate endosomal escape of the nanoparticles. Ionizable Lipids promote endosome escape and reduce toxicity of lipid nanoparticles (LNP).
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