Designer peptide delivery systems for gene therapy

Gene therapy has long been hailed as a revo- lutionary approach for the treatment of genetic diseases. The enthusiasm that greeted the harnessing of viruses for therapeutic DNA delivery has been tempered by concerns over safety. These concerns led to the development of alternative strategies for nucleic acid delivery to cells. One such strategy is the utilization of cationic peptides for the condensation of therapeutic DNA for delivery to its target. However, success of DNA as a therapy relies on its delivery to the nucleus of target cells, a process that is complicated by the many hurdles encountered following systemic administration. Non-viral peptide gene delivery strategies have sought inspiration from viruses in order to retain DNA delivering potency, but limit virulence. This review summarizes the progression of peptide-based DNA deliv- ery systems, from rudimentary beginnings to the recent development of sophisticated multi-functional vectors that comprise distinct motifs with dedicated barrier eva- sion functions. The most promising peptides that achieve cell membrane permeabilization, endosomal escape and nuclear delivery are discussed.