**1. Introduction**

614 Non-Viral Gene Therapy

Zeng, J., X. Wang and S. Wang. 2007. Self-assembled ternary complexes of plasmid DNA,

delivery into neurons. Biomaterials 28, no. 7: 1443-51.

low molecular weight polyethylenimine and targeting peptide for nonviral gene

In its most simplistic sense, gene therapy involves the delivery and expression of DNA by target cells so as to produce a therapeutic protein. In the case of RNA interference (RNAi), it is to shut off or silence the expression of a particular target protein. In order to exert its effects, the nucleic acid must first reach its intended site of action. DNA molecules (frequently as plasmids, which are circularised DNA) have to gain nuclear entry to access the transcription machinery. Conversely, RNAi molecules such as small interfering RNA (siRNA), short hairpin RNA (shRNA) and micro RNA (miRNA) will need to accumulate within the cytoplasm, although shRNA-encoding plasmids will require prior nuclear access before transcription into shRNA. However, if administered alone, a great majority of the nucleic acids will be degraded en route, leading to a lost of therapeutic potential. This then necessitates the development of vectors that protect and deliver nucleic acids to their target site. Arguably, it is the lack of safe and efficient delivery systems, rather than suitable therapeutic molecules that is limiting the success of gene therapy.

In this chapter, we start by examining how issues at the cellular level have shaped the design of modern, multifunctional vectors. We then briefly review the various types of gene delivery system, focusing on peptides as a promising class of non-viral vector. We will concentrate on the delivery of plasmids since the phenomenon of RNAi is relatively recent (Fire et al., 1998). As such, many strategies for RNAi delivery are adapted from DNA delivery technology.
