Nature Nanotech. http://doi.org/s3p (2014)

The concurrent silencing of multiple genes requires highly efficient siRNA delivery and, until now, has only been observed in hepatocytes. Now, Daniel Anderson and colleagues demonstrate the efficient delivery of siRNA to endothelium, both in vitro and in vivo, using a polymer–lipid nanoparticle delivery system. These siRNA-loaded nanoparticles simultaneously silence five endothelial genes and reduce endothelial gene expression by 90% at low doses (0.10 mg kg−1). In the case of hepatocytes, pulmonary immune cells and peritoneal immune cells minimal reduction in gene expression was seen. The in vivo efficacy of this polymeric delivery system is demonstrated in animal models in the therapeutic areas of emphysema and lung cancer. In the latter, a reduction in both primary tumour growth and lung metastases is seen. The potent delivery of siRNA, in particular to pulmonary endothelial cells, is evident from the long duration (several weeks) of gene silencing in these models. Although the precise mechanism involved in the multiple silencing has yet to be determined, Anderson and colleagues propose the involvement of serum proteins.