Angew.Chem.Int.Ed.http://dx.doi.org/10.1002/anie.201406764(2014)

Credit: © 2014 WILEY

Short interfering RNAs (siRNAs) are double-stranded pieces of RNA that can act as antiviral agents or can be used to reduce the expression of specific genes via RNA interference pathways. The potential for altering complex biological systems makes them interesting therapeutic candidates. However, siRNA is not easily taken up by cells, therefore therapies based on exogenous siRNA require a mechanism to transfer siRNA across the cell membrane. Although a variety of viral, lipid and polymer vectors have been developed, delivery efficiency is often low and can vary depending on the type of cell being targeted.

Ling Peng from Aix-Marseille University, France, and co-workers have developed a nanocarrier for delivering siRNA into cells that is based on an amphiphilic dendrimer. In water the dendrimer self-assembles into vesicle-like dendrimersomes; however, on addition of siRNA the dendrimersomes rearrange into smaller micelle structures. This rearrangement increases the positively charged surface area of the micelle and thereby increases the potential for stabilizing interactions between the dendrimer and negatively charged siRNA. These interactions induce the micelles and siRNA to condense and form colloidal nanoparticles. Computational studies confirm the adaptive rearrangement and assembly mechanism, and initial experiments established that the nanoparticles could protect the siRNA from degradation and were rapidly taken up by cells.

Next, the team tested the efficacy of the nanoparticles for releasing siRNA inside the cell. Experiments with cancer cell lines showed that siRNA could be effectively delivered, and that the production of both messenger RNA and protein targets could be reduced. Further experiments showed that siRNA could also be delivered into both stem cells and primary cells. In a final demonstration, the team showed that the siRNA/dendrimer nanoparticles could reduce messenger RNA and protein expression levels in a prostate cancer mouse model. This led to the effective inhibition of tumour growth without discernible toxicity.