Nanocarrier-cell interaction: exploring the cell surface & intracellular trafficking

PhD ceremony: Mr. Z.U. Rehman, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Nanocarrier-cell interaction: exploring the cell surface & intracellular trafficking

Promotor(s): prof. D. Hoekstra

Faculty: Medical Sciences

Gene therapy involves the delivery of genetic material, such as genes or siRNA, into the cell for therapeutic purposes. Current delivery systems are broadly classified as viral- or non-viral vectors. Lipoplexes (mixture of cationic lipids and DNA) and polyplexes (mixture of cationic polymers and DNA) are the types of non-viral vectors that gained considerable interest in recent years. Elucidating the extra- and intracellular processing of these lipo/polyplexes (‘nanocarriers’) will help us to understand the underlying delivery mechanisms. This knowledge, in turn, is essential to further improve delivery and transfection efficiency and as a result the therapeutic applications. In this thesis we demonstrate that cellular extensions, known as filopodia, are actively engaged in ‘capturing’ nanoparticles. The underlying mechanism is revealed in molecular detail, bearing an interesting analogy as to how viruses and bacteria interact with cells. We also show how endocytic pathways can be manipulated to facilitate the efficiency of nanocarriers to release their nucleic acid cargo within the cells, and avoid delivery into lysosomes, the degradation compartment of the cell. Moreover, by using live cell imaging we were the first to directly visualize the movement of nanocarriers along filopodia, and the more or less ‘explosive’ delivery of nucleic acid contents inside the cell.