FIG. 1.

RNA therapeutics, including PS ASOs, siRNAs, PMO ASOs, PNA ASOs, and other oligonucleotides, are too large, too charged, and/or too hydrophilic to passively diffuse across the billion-year-old cell membrane lipid bilayer, but instead require a TD to drive uptake by endocytosis. However, endosomes also comprise a lipid bilayer, and 1% or less of endocytosed RNA therapeutics escape the endosome. Thus, endosomal escape is the rate-limiting delivery step. TD, targeting domain; PS, phosphorothioate; ASO, antisense oligonucleotide.