Lipid-based nanotherapeutics for siRNA delivery

Abstract

RNA interference (RNAi) is a specific gene-silencing mechanism triggered by small interfering RNA (siRNA). The application of RNAi in the clinic requires the development of safe and effective delivery systems. Inspired by progress with lipid-based systems in drug delivery, efforts have been dedicated to the development of liposomal siRNA delivery systems. Many of the lipid-based delivery vehicles self-assemble with siRNA through electrostatic interactions with charged amines, generating multi-lamellar lipoplexes with positively charged lipid bilayers separated from one another by sheets of negatively charged siRNA strands. Internalization of lipid-based siRNA delivery systems into cells typically occurs through endocytosis; accordingly, delivery requires materials that can facilitate endosomal escape. The size of the carrier is important as carriers <100 nm in diameter have been reported to have higher accumulation levels in tumours, hepatocytes and inflamed tissue, whereas larger particles tend to be taken up by Kupffer cells or other components of the reticuloendothelial system (RES). To reduce RES uptake and increase circulation time, carriers have been modified on the surface with hydrophilic materials, such as polyethyleneglycol. Herein, we review the molecular and structural parameters of lipid-based siRNA delivery systems.

Fig. 1

A schematic representation of the fusion of a multilamellar small interfering RNA lipoplex with the cell membrane. The positively charged lipid bilayer adsorbs to the negatively charged surface of the cell, resulting in either an endocytosis process or by fusion of the lipoplex with the cell membrane, thereby releasing the nucleic payload into the cytosol [38]. During the process, the lipid membrane is stressed and lipids are freed to the intracellular and extracellular compartments.

Fig. 2

Multilamellar structure of cationic lipid and small interfering RNA (siRNA) lipoplexes. SiRNA double strands adsorb to the positively charged surfaces of lipid bilayers, to form a multilamellar structure in which, ~3.7-nm thick [65] lipid bilayers are separated ~2 nm apart from each other by siRNA strands [68].

Fig. 3

Lessons learned from structural modifications of DOTMA acting as a transfection agent.