Delivery of RNAi Therapeutics to the Airways—From Bench to Bedside

Qiu, Yingshan; Lam, Jenny K. W.; Leung, Susan W. S.; Liang, Wanling

Surface adhesion is the first step of cellular entry. There are various endocytic mechanisms involved in the cellular uptake of macromolecules, which subsequently influence their intracellular trafficking and delivery efficiency [50] [51] [52] [53] [54] [55] . The clathrin-dependent endocytosis is the most common route of cellular entry for macromolecules [56] . Following cell entry, the RNAi molecules are entrapped in the early endosomes where progressive acidification occurs. The late endosomes then fuse with the lysosomes, which contain hydrolases that degrade the RNAi molecules [56, 57] . The RNAi molecules must escape from endosome at early stage to exert their biological effect. Strategies of endosomal escape have been reviewed in other literatures [58] [59] [60] [61] . For shRNA or miRNA vectors, nuclear entry is an additional barrier which is particularly challenging due to the presence of nuclear membranes that are impermeable to most substances except small non-polar molecules [62] . Non-viral vectors are inefficient in delivering DNA into the nucleus. Some viruses are evolved to transport their genome into the nucleus; hence, they become attractive DNA carriers to improve transduction efficiency. However, poor safety profile, high production cost and the risk of immunogenicity [63] limited the applications of viral vector mediated RNAi to laboratory tool.