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Nucleic Acid Ther. 2019 Jun 3. doi: 10.1089/nat.2019.0794. [Epub ahead of print]

Lipid Conjugates Enhance Endosomal Release of Antisense Oligonucleotides Into Cells.

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1 Department of Core Antisense Research, Ionis Pharmaceuticals, Inc., Carlsbad, California.
2 Department of Medicinal Chemistry, Ionis Pharmaceuticals, Inc., Carlsbad, California.


Antisense oligonucleotides modified with phosphorothioate linkages (PS-ASOs) can enter cells via endocytic pathways and must escape from membraned organelles to reach target RNAs. We recently found that membrane destabilization induced by different lipid species contributes to PS-ASO release from late endosomes (LEs). In this study, we characterized intracellular uptake, trafficking, and activities of PS-ASOs conjugated with different lipid species. We found that palmitic acid-, tocopherol-, and cholesterol-conjugated PS-ASOs have increased protein binding and enhanced intracellular uptake compared to unconjugated PS-ASOs. Similar to the parental PS-ASO, the lipid-conjugated PS-ASOs traffic from early to LEs without incorporation into lipid droplets. Unlike parental PS-ASOs, the lipid-conjugated PS-ASOs tend to remain associated with plasma or endosomal membranes, and this appears to influence their release from endosomes. The lipid-conjugated PS-ASOs were released more rapidly than parental PS-ASO. These results suggest that lipid conjugation enhances the interactions of PS-ASOs with proteins or membranes, in turn facilitating intracellular trafficking and endosomal release.


antisense oligonucleotides; endosomal release; free fatty acids; intracellular trafficking; lipid conjugates


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