Unravelling the mechanisms of recognition and internalization of nanoparticles by cells

Nanoparticles have great potential for drug delivery (nanomedicine), because of their size (few to hundreds of nanometers). They are bigger than molecular drugs, so they cannot diffuse into the cell. Instead they enter cells through specialized cell pathways, similar to those used by natural nano-sized objects, like proteins and viruses. This gives nanoparticles the potential to be used to deliver drugs only to specific cells, thus improving efficacy and reducing side-effects. Several nanomedicines have already reached the market, but the targeting to specific cells can still be improved and the mechanism by which nanoparticles are processed and internalized by cells often remains unclear. Most research studies well-known uptake pathways, however it might be that unconventional mechanisms are involved in the entry of nanoparticles into cells. In this thesis, several different methods have been used to study the role of known pathways in the uptake of nanoparticles. In particular, the impact of nanoparticle charge and mechanical properties on the mechanism of uptake has been investigated. Moreover, for the first time in this field, we have applied a method in which all cellular components can be screened for their involvement in nanoparticle uptake. In this way, we have been able to discover novel components and studied their role. Our results showed that nanoparticle uptake mechanisms depend on nanoparticle properties, but are also affected by the presence of biomolecules which adsorb on the nanoparticles, which can interact with multiple cell receptors. At a broader level, our results illustrate the complexity of nanoparticle-cell interactions