Biology Reference
In-Depth Information
Chapter 4
Intracellular Delivery Considerations
for RNAi Therapeutics
Yu Zhu , Jing Li , and David Oupický
Abstract
Intracellular delivery of the wide range of RNAi therapeutics is a complex
process that remains to be fully understood and mastered. This chapter discusses the
current understanding of the process of intracellular delivery of RNAi triggers from
multiple perspectives. The delivery requirements are primarily determined by the
properties and intracellular site of action of the RNAi molecule. Main intracellular
barriers to nonviral delivery of siRNA, shRNA, and miRNA are discussed, together
with the latest methods to overcome them. The barriers covered include cellular
uptake, endosomal escape, cytoplasmic trafficking, nuclear entry, and therapeutic
cargo release from delivery vectors.
4.1
Introduction
Since RNA interference (RNAi)-based gene silencing by double-stranded RNA was
first described in 1998 [
1
], the field of RNAi-mediated gene therapy has been
quickly developing. However, the clinical application of RNAi-based therapeutics
is hindered by the lack of adequate delivery methods. Not only are nucleic acids
subject to degradation by a host of nucleases [
2
], their polyanionic nature makes
translocation across cellular membranes difficult. Further compromising RNAi
efficacy is the often-inadequate delivery to the specific subcellular compartments
and incorporation into the RNAi machinery. The application of RNAi triggers as a
potential clinical agent requires proper design and development of effective and
safe delivery vectors. This chapter focuses on the intracellular trafficking of differ-
ent RNAi triggers and recent developments in the design of delivery vectors capable
of breaking down intracellular delivery barriers.
Y. Zhu • J. Li • D. Oupický (
*
)
Department of Pharmaceutical Sciences , Wayne State University ,
259 Mack Avenue , Detroit , MI , USA
e-mail: oupicky@wayne.edu
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