Promotie P. Kowalski:Lipid carriers for endothelial-specific delivery of siRNA. From particle development to attenuation of inflammation

Nanotechnology has generated a significant impact in nearly every aspect of science, spurring new therapies that hold the promise to improve health care. The aim of this research was the development of advanced nano-carrier systems for endothelial-specific in vivo delivery of short interfering RNAs (siRNAs) to improve existing anti-inflammatory therapies, which often carry a substantial risk of systemic toxicity. siRNAs are double-stranded RNA molecules (20-25 base pairs in length) that are used to transiently switch off the expression of specific genes. Therapeutic potential of siRNAs have been well recognized, and as a result they are being translated into the clinic with an unprecedented speed. The ultimate goal, achieving siRNA-based therapies for life-threatening or debilitating diseases, can, however, not be attained without improving the safety, efficiency and target specificity of siRNA delivery systems.Endothelial cells are an attractive target for anti-inflammatory therapy by virtue of their active engagement in the inflammatory process and their pivotal role in the pathology of (chronic) inflammatory diseases, including atherosclerosis, diabetes and sepsis. We designed siRNA carriers based on cationic lipid SAINT-C18, that can entrap siRNA and allow its selective delivery into inflammation activated endothelium in vivo. Using nano-carriers called SAINT-O-Somes containing a NFκB specific siRNA and targeted to an inflammatory adhesion molecule (VCAM-1), expressed on the surface of endothelial cells, we demonstrated selective interference with NFκB signaling in inflamed endothelium in vivo. Our studies provided proof of concept that endothelial-specific siRNA-based anti-inflammatory interventions can offer an alternative approach to therapeutically address inflammatory diseases.