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Review
. 2014 Sep 19;4(12):1211-32.
doi: 10.7150/thno.8491. eCollection 2014.

Functional Nanostructures for Effective Delivery of Small Interfering RNA Therapeutics

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Free PMC article
Review

Functional Nanostructures for Effective Delivery of Small Interfering RNA Therapeutics

Cheol Am Hong et al. Theranostics. .
Free PMC article

Abstract

Small interfering RNA (siRNA) has proved to be a powerful tool for target-specific gene silencing via RNA interference (RNAi). Its ability to control targeted gene expression gives new hope to gene therapy as a treatment for cancers and genetic diseases. However, siRNA shows poor pharmacological properties, such as low serum stability, off-targeting, and innate immune responses, which present a significant challenge for clinical applications. In addition, siRNA cannot cross the cell membrane for RNAi activity because of its anionic property and stiff structure. Therefore, the development of a safe, stable, and efficient system for the delivery of siRNA therapeutics into the cytoplasm of targeted cells is crucial. Several nanoparticle platforms for siRNA delivery have been developed to overcome the major hurdles facing the therapeutic uses of siRNA. This review covers a broad spectrum of non-viral siRNA delivery systems developed for enhanced cellular uptake and targeted gene silencing in vitro and in vivo and discusses their characteristics and opportunities for clinical applications of therapeutic siRNA.

Keywords: gene delivery; gene silencing; nanoparticles; non-viral vectors; small interfering RNA (siRNA)..

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Comparison of the intracellular processing of cleavable and non-cleavable siRNA-polymer conjugates for RNAi activity.
Figure 2
Figure 2
Schematic illustration of the preparation and delivery strategies of different siRNA-polymer conjugates.
Figure 3
Figure 3
(a) Synthetic scheme of the construction of reductively dissociable siRNA-polymer nanogels (MCN), (b) hydrodynamic mean diameters (bar graph, left panel) and zeta potentials (square, right panel) of different siRNA complexes, (c) visualization of released siRNA from nanogels in a heparin solution while increasing the glutathione (GSH) concentration, and (d) semi-quantitative RT-PCR analysis of intracellular VEGF mRNA in cells after the transfection of different siRNA complexes. Human β-actin mRNA was used as a control. UC denotes siRNA/LPEI complexes, CN represents siRNA/thiol-grafted LPEI complexes, and MCN denotes thiolated siRNA/thiol-grafted LPEI complexes. Copyright 2012 Wiley-VCH.
Figure 4
Figure 4
A schematic design of liposomes encapsulating siRNA.
Figure 5
Figure 5
Strategy to load siRNA on inorganic nanoparticles: (a) Chemical conjugation and adsorption of siRNA on a single nanoparticle surface; (b) electrostatic interaction of siRNA and cationic shell on (b) a single nanoparticle and (c) cationic polymer-coated nanoparticle clusters; (d) layer-by-layer assembly of siRNA and cationic polymers on a single nanoparticle surface.
Figure 6
Figure 6
(a) Schematic illustrations of the construction of a siRNA/PEI/PAH-Cit/CS-AuNP nanoparticle and the pH-responsive release of siRNA, (b) quantitative analysis of a released siRNA from siRNA/PEI/PAH-Cit/CS-AuNP nanoparticle in a pH environment ranging from 7.4 to 5.5. (c) MDR1 mRNA levels in cells treated with bPEI (25 kDa)/siRNA complexes and siRNA/PEI/PAH-Cit/CS-AuNP nanoparticles. X is scrambled siRNA and GAPDH mRNA was used as a control. Copyright 2012 American Chemical Society.
Figure 7
Figure 7
(a) Synthetic scheme of the preparation and polymeric condensation of siRNA microhydrogels: AFM images of (b) different siRNA-based structures and (c) their polymeric condensation with a cationic oligomer. The inset in YY-siRNA panel is a high-magnification 3D AFM images. (d) Dose-dependent GFP suppression effect of different siRNA/LPEI complexes in GFP-overexpressed MDA-MB-435 cells. Copyright 2011 American Chemical Society.

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