Delivery of Macromolecular Therapeutics: Tackling a Billion Year Old Barrier

All macromolecular therapeutics, including ASOs, siRNAs, peptides, proteins, CRISPR, mRNA and non-viral DNA vectors, are taken up into cells by endocytosis. However, less than 1% to none of the endocytosed therapeutic cargo escapes into the cytoplasm and nucleus of the cell. Thus, for all macromolecular therapeutics, endosomal escape remains the rate-limiting delivery step that prevents their effective use to treat cancer, pandemic influenza, and other diseases. Our research is focused on addressing this problem by developing new chemistry to synthesize novel universal endosomal escape domains (uEEDs) with the goal of enhancing the endosomal escape of macromolecular therapeutics by 10- to 100-fold in the absence of toxicity.