Lipid-Like Delivery Materials for Efficient siRNA Delivery - Nanotechnology for the Delivery of Therapeutic Nucleic Acids - page 154

7.1 Introduction

Before the discovery that RNA could regulate gene expression via
RNA interference (RNAi) in 1998,

1

RNA was viewed primarily as an
intermediary between DNA and protein. Since this breakthrough,
the role of RNA in biology and medicine has been greatly expanded.
RNA has been applied not only as a tool in basic research but also as
a clinical therapeutic modality. The utility of RNA in these settings
requires successful delivery of RNA into the cytoplasm of the
cells of interest. , delivery necessitates that RNA pass through

the anionic and amphiphilic cell membrane so that it can interact
with the cytosolic RNA induced silencing complex (RISC) to initiate
gene silencing. The physical properties of RNA render this feat
challenging; specifically, RNA is large (~13 kDa for a double-stranded
21-mer) and negatively charged.

In vitro

, successful delivery is even
more difficult. Before entering the cytoplasm, molecules must interact
with the correct cell type while avoiding degradative nucleases and
phagocytotic cells in the bloodsteam

In vivo

2

(Fig. 7.1) . To overcome these
obstacles, scientists have designed synthetic delivery vehicles from
gold, cholesterol, polymers, and many other materials.

3

One subset

that has delivered siRNA to cells efficiently in vitro and in vivo is a

class of amphiphilic lipid-like structures, termed “lipidoids.”

Figure 7.1 Physiological barriers to small RNA delivery. delivery

requires that vehicles ferry RNA to the correct cell type while
avoiding phagocytotic uptake, degradative nucleases, and
inadvertent immune stimulation. If the carrier successfully
completes this task, it must then transport the large, anionic
nucleic acids across the negative lipid bilayer. Reproduced with
permission from Ref. [2].

In vivo