Rigid nanoparticle-based delivery of anti-cancer siRNA: challenges and opportunities

Abstract

Gene therapy is a promising strategy to treat various genetic and acquired diseases. Small interfering RNA (siRNA) is a revolutionary tool for gene therapy and the analysis of gene function. However, the development of a safe, efficient, and targetable non-viral siRNA delivery system remains a major challenge in gene therapy. An ideal delivery system should be able to encapsulate and protect the siRNA cargo from serum proteins, exhibit target tissue and cell specificity, penetrate the cell membrane, and release its cargo in the desired intracellular compartment. Nanomedicine has the potential to deal with these challenges faced by siRNA delivery. The unique characteristics of rigid nanoparticles mostly inorganic nanoparticles and allotropes of carbon nanomaterials, including high surface area, facile surface modification, controllable size, and excellent magnetic/optical/electrical properties, make them promising candidates for targeted siRNA delivery. In this review, recent progresses on rigid nanoparticle-based siRNA delivery systems will be summarized.

Keywords: Gene delivery; Gene therapy; Nanoparticles; RNA interference (RNAi); Small-interfering RNA (siRNA).

Figure 1

Schematic illustration of the EPR effect and “active targeting process”. Blood flow is the essential driving force for nanocarrier delivery.

Figure 2

Schematic illustration of siRNA delivery and the mechanism of RNA interference. The delivery process is divided into two phases. Phase I: Nanocarrier based siRNA loading. Phase II: intracellular siRNA release and gene silencing. (a) Internalization of siRNA nanocomplex by endocytosis; (b) the nanocomplex escapes from endosome while (c) avoiding lysosomal destruction. (d) Nanocomplex disassembles and then siRNA is released into cytoplasm; (e) siRNA and mRNA are incorporated with RISC complex for mRNA degradation.

Figure 3

a) Schematic illustration of the preparation of Alkyl-PEI2k-IOs/siRNA complexes. b) The in vivo optical images of gene-silencing effect by Alkyl-PEI2k-IOs/siRNA complexes in 4T1 cells expressing firefly luciferase (Adapted with permission from Liu et al., 2011b).

Figure 4

a) Schematic illustration of the preparation of ZnS-AgInS₂ QDs for simultaneous imaging and delivery of siRNA. b) In vitro testing of ZAIS QDs-siRNA nanocomplexes against EGFP in U87-EGFP glioblastoma cells. The fluorescence image showed that the silenced cells have internalized the siRNA-QDs (red) (Adapted with permission from Subramaniam et al., 2012).

Figure 5

(a) Au nanoparticles modified with pH sensitive macromolecules. (b) UV absorbance changes of the acid-responsive nanoparticles before (red) and after (blue) acid hydrolysis. (c) Three-dimensional SD-OCT images showed the optical coherence property changes of the acid-responsive nanoparticles with acid-hydrolysis. (d) Gene silencing efficiency of the acid-responsive nanoparticles in vitro under a tumor-mimicking condition in eGFP-expressing NIH 3T3 cells (Adapted with permission from Shim et al., 2010).

Figure 6

a) Illustration of the CaP nanoparticles modified with lipid and non-targeted/targeted ligands. (b) TEM images of functionalized CaP nanoparticles. c) In vivo biodistribution of CaP nanoparticles carrying Texas Red-siRNA in subcutaneous A549 tumor model. d) The oncogene silencing effect in subcutaneous H460 tumor model (Adapted with permission from Yang et al., 2012).