It is a great challenge for nanomedicine to develop novel dendrimers with maximum therapeutic potential and minimum side-effects for drug and gene delivery. As delivery vectors, dendrimers must overcome lots of barriers before delivering the bio-agents to the target in the cell. Extensive experimental investigations have been carried out to elucidate the physical and chemical properties of dendrimers and explore their behaviors when interacting with biomolecules, such as gene materials, proteins, and lipid membranes. As a supplement of the experimental techniques, it has been proved that computer simulations could facilitate the progress in understanding the delivery process of bioactive molecules. The structures of dendrimers in dilute solutions have been intensively investigated by monomer-resolved simulations, coarse-grained simulations, and atom-resolved simulations. Atomistic simulations have manifested that the hydrophobic interactions, hydrogen-bond interactions, and electrostatic attraction play critical roles in the formation of dendrimer–drug complexes. Multiscale simulations and statistical field theories have uncovered some physical mechanisms involved in the dendrimer-based gene delivery systems. This review will focus on the current status and perspective of theoretical and computational contributions in this field in recent years. (275 references)

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.

Langevin dynamics simulations are employed to study the shape transformation of a two-dimensional vesicle induced by active particles both inside and outside. We find that the shape of the vesicle changes from circle, to capsule, and eventually to dumbbell with the enhancement of the particle activity. Under the cooperation between the inside and the outside active particles, such significant shape transformation is realized by tuning the activity in a small range. And unexpectedly, the fluctuations of the capsule and the dumbbell shapes are not completely random but mostly along the direction of the short axis. In the situation of strong activity, the inside of the dumbbell vesicle is analogous to a system of two chambers, which are connected by a narrow channel. Intriguingly, we observe the vibration of the channel width, accompanied with the exchange of active particles between the two chambers. We also find that dynamical manipulation of the vesicle shape is possible through tuning the particle activity dynamically. This work provides new ideas to the control of the vesicle morphology and new insights into the dynamics in the vesicle’s shape transformation.