Abstract

RNA therapeutics have shown great promise in treating human liver and some CNS disease. Unfortunately, other indications, such as cancer and pandemic viral disease, remain recalcitrant to RNA therapeutics. Unlike small molecule therapeutics that are designed to passively diffuse across the cell membrane’s lipid bilayer, RNA therapeutics are too large, too charged and/or too hydrophilic to cross this billion year old evolutionary defense and instead are taken up by various forms of endocytosis. However, endosomes are also composed of a lipid bilayer that prevents their escape into the cytoplasm. Indeed, only ~1% or less of endocytosed RNA therapeutics escape from the endosome, leaving >99% entrapped inside of endosomes. Unfortunately, there are currently no acceptable solutions to the endosomal escape problem. Given the magnitude of impact that solving the endosomal escape problem would have on the entire RNA therapeutics field (and perhaps others), if it was easy, it would have already been solved. Moreover, the more we work on it, the greater the appreciation I have for how difficult it will be to successfully overcome in a non-toxic manner. Consequently, before RNA therapeutics can be used to treat widespread human disease, the rate-limiting delivery problem of endosomal escape must be solved. Our approach to addressing the endosomal escape problem has been to chemically synthesize novel universal Endosomal Escape Domains (uEEDs) that are biomimetics of the mechanism that enveloped viruses use to solve their endosomal escape.