Proton sponge or membrane fusion? – Endosomal escape of siRNA polyplexes unveiled by MD simulations

Introduction: Cationic polymers can encapsulate RNA through electrostatic interactions, safeguard the cargo in a biological milieu, and enable cellular uptake. However, the efficiency of RNA carriers in general is limited by insufficient endosomal escape (EE). Better understanding of the mechanisms that enable EE is therefore crucial to improving the design of delivery vehicles. Here, we used molecular dynamics (MD) to study the interaction of siRNA polyplexes within an endosomal vesicle. We were able to link interaction mechanisms observed in silico to differences between the particles detected in vitro.