Insights into the endosomal escape mechanism via investigation of dendrimer-membrane interactions

Understanding the mechanism of the escape of non-viral vectors from endosomes is critically important for the development of new gene delivery systems. Coarse-grained molecular dynamics simulations of responsive dendrimers interacting with tensionless and tense lipid membranes were performed to give insight into the gene escape mechanism. It was found that the insertion of a charged dendrimer into a membrane is facilitated by the asymmetric distribution of charged lipids and the strongly charged dendrimer can cause a breakdown of membrane asymmetry. Furthermore, dendrimer adsorption could lead to the drop of critical stress required to disrupt the membrane. We propose that a fundamental way for nanoparticles to penetrate through targeted membranes is endowing them with capabilities to tune the local membrane tension. Finally, an escape mechanism of delivered gene materials from an endosome was suggested: a cooperation between global effect, resulting from osmotic pressure and the increase of dendrimer size in the endosome, and local effects caused by the electrostatic adsorption of dendrimers.