Knocking down barriers: advances in siRNA delivery - PubMed (original) (raw)

Review

Knocking down barriers: advances in siRNA delivery

Kathryn A Whitehead et al. Nat Rev Drug Discov. 2009 Feb.

Erratum in

Abstract

In the 10 years that have passed since the Nobel prize-winning discovery of RNA interference (RNAi), billions of dollars have been invested in the therapeutic application of gene silencing in humans. Today, there are promising data from ongoing clinical trials for the treatment of age-related macular degeneration and respiratory syncytial virus. Despite these early successes, however, the widespread use of RNAi therapeutics for disease prevention and treatment requires the development of clinically suitable, safe and effective drug delivery vehicles. Here, we provide an update on the progress of RNAi therapeutics and highlight novel synthetic materials for the encapsulation and intracellular delivery of nucleic acids.

PubMed Disclaimer

Figures

Figure 1

Figure 1. The mechanism of RNA interference.

Long double-stranded RNA (dsRNA) is introduced into the cytoplasm, where it is cleaved into small interfering RNA (siRNA) by the enzyme Dicer. Alternatively, siRNA can be introduced directly into the cell. The siRNA is then incorporated into the RNA-induced silencing complex (RISC), resulting in the cleavage of the sense strand of RNA by argonaute 2 (AGO2). The activated RISC–siRNA complex seeks out, binds to and degrades complementary mRNA, which leads to the silencing of the target gene. The activated RISC–siRNA complex can then be recycled for the destruction of identical mRNA targets.

Figure 2

Figure 2. Physiological barriers to the systemic delivery of small interfering RNA (siRNA) nanoparticles.

An injected nanoparticle must avoid filtration, phagocytosis and degradation in the bloodstream (a); be transported across the vascular endothelial barrier (b); diffuse through the extracellular matrix (c); be taken up into the cell (d); escape the endosome (e); and unpackage and release the siRNA to the RNA interference (RNAi) machinery (f).

Figure 3

Figure 3. Two common small interfering RNA (siRNA) modifications used for therapeutic applications.

a | The 2′-_O_-methyl sugar modification prevents activation of the Toll-like receptor 7 immune response and confers enzymatic resistance to the siRNA molecule. b | The conjugation of cholesterol to the sense strand of an siRNA duplex improves delivery of naked siRNA to certain cellular targets, including hepatocytes. The cholesterol conjugate is shown in red, and the linker is shown in green.

Figure 4

Figure 4. Synthetic materials for small interfering RNA (siRNA) delivery.

a | A representation of stable nucleic acid–lipid particles (SNALPs), which are liposomes comprising cationic lipids, non-ionic lipids and polyethylene glycol (PEG). siRNA is contained in the hydrophilic interior of the particle. b | Polyethyleneimine is used to fabricate both linear and branched polymeric delivery agents. c | A cyclodextrin-based delivery agent. d | The lipidoid 98N12-5(1).

Similar articles

Cited by

References

    1. Fire A, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391:806–811. - PubMed
    1. Elbashir SM, et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001;411:494–498. - PubMed
    1. McCaffrey AP, et al. Gene expression: RNA interference in adult mice. Nature. 2002;418:38–39. - PubMed
    1. Morrissey DV, et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nature Biotech. 2005;23:1002–1007. - PubMed
    1. Okumura A, Pitha PM, Harty RN. ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner by blocking Nedd4 ligase activity. Proc. Natl Acad. Sci. USA. 2008;105:3974–3979. - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources