Figure 3: The numerology of endosomal escape.
Tris-GalNAc binding to liver ASGPR (∼106/hepatocyte) induces endocytosis (∼15 min) where a small fraction of the siRNA or ASO cargo escapes into the cytoplasm to induce selective RNA drug responses. In contrast, targeting non-hepatic cell surface receptors (104–105) that have a much slower rate of endocytosis (∼90 min) has proven extremely difficult. Assuming there is no endosomal escape advantage in ASGPR endosomes, ASGPR brings in ∼100-fold more siRNAs/ASOs into hepatocytes than is mathematically possible in any other ligand–receptor pair. Consequently, development of next-generation RNA-based therapeutics needs to incorporate new chemistries, materials and/or mechanisms of enhancing endosomal escape ∼100-fold.
