Delivery of Genes and Oligonucleotides

This chapter highlights the major nucleic acid delivery mechanisms as well as best practices in delivery vector design and development. Nucleic acids encounter a number of formidable obstacles between the site of administration and the site of action. Nonetheless, the majority of genes and oligonucleotides currently under development are formulated for systemic administration. Even after overcoming systemic barriers and entering the target cells, a vector must still make its cargo available for expression (gene delivery) or to silence its target mRNA. Two barriers in achieving this task are escape from endosomes and unpackaging of the carrier from the nucleic acid. A wide variety of polymer and lipid chemistries has been explored as potential carriers for therapeutic nucleic acids without a consensus emerging as to the chemical structures best suited for the task. Formulations have advanced to the clinic from both main camps: highly charged, primarily hydrophilic polymers, and amphiphilic lipids.