In most cases, LNPs accumulate in the liver suggesting that targeted delivery to the liver is trivial. However, when using two different LNP formulations, it was uncovered that they had different mechanisms of delivery. Traditionally regarded as being taken up by hepatocytes, one LNP formulation, upon accumulating in the liver, could not be delivered to these same liver hepatocytes. In a study by Siegwart, D., et. al, researchers created two LNP formulations differing only by the ionizable cationic lipid to determine what factors affect the location within the liver. The physical characteristics of LNPs such as particle size, surface charge and pKa were compared and evaluated. The molar weight of each ionizable lipid was the same, and the size, surface charge and RNA encapsulated was similar as well. Additionally, the pKa value was the same. However, the number of hydrophobic branches for each ionizable lipid was unique to each (5 vs. 3). Ultimately, it was found that ApoE and albumin were key mediators of the difference in uptake by hepatocytes or Kupffer cells and that altering the chemistry of the amino lipid was the likely cause of this. Gene expression was only observed in hepatocytes after Kupffer cells were destroyed.
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