Arbutus Biopharma
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Re: Chime in on thisMy guess. LNP delivery gives very good release from endosomes. The evolution of LNP design by Tekmira was toward better endosome release. The mechanism, which involves pH dependent ionization of LNP lipids, mimics mechanisms used by viruses to efficiently escape endosomes to cytoplasm. GalNAc delivery gives rapid, focused cell uptake to hepatocytes, but release of siRNA to cytoplasm is very slow. You need to load much more into the endosomes to get enough released. Also relevant here, siRNA delivered using GalNAc conjugation must be stabilized by extensive chemical modification, whereas siRNA delivered by LNP can be unmodified. The greater stability to nucleases and slow continuous release from endosomes explains the greater durability of activity for the GalNAc conjugated siRNA.
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