In gene delivery applications, one of the first steps to ensure transfection of the genetic material is promoting the interaction with the negatively charged cell membranes. Due to the like-charged character of DNA and cell membranes, polycations are often used to mediate this interaction. The behaviour of these systems is sometimes counterintuitive and dependent on a number of interrelated factors, including membrane charge and composition, that are, in turn, dependent on cell type and pathology. For instance, upon tumorogenesis the membrane charge becomes more negative. Other features such as polycation structure, charge and concentration also impact on the polyplex-membrane interaction.

Due to the inherent complexity of the system, much remains to clarify, especially because most previous work was focused on the cation-mediated adsorption with surfaces with charge densities much higher than those of cell membranes.

In this work Monte Carlo simulations within the primitive model allows to establish the optimal conditions for the adsorption of DNA-polyplexes, ranging from undercharged to overcharged, upon responsive surfaces of different charge density mimicking healthy and tumoral cell membranes. Briefly, it was found that polyplex adsorption is favoured in the more negatively charged membranes, for polyplexes formed with longer polycations and at intermediate polycation concentrations.