Lipopolyplexes have received extensive attention lately in gene therapy delivery. However, the interactions between the polyplex and the liposome and their underlying molecular mechanisms remain to be elucidated. Here, we adopted a simple model, mainly to illustrate the impact of polyplex charge density on the self-assembly of liposomes (containing DOPE and CHEMS lipids) using coarse-grained molecular dynamics simulations. Our simulation results show that when the charge density increases in the polyplex, more lipids, especially CHEMS (a negatively charged helper lipid) lipids, are attracted to the polyplex (positively charged) surface, and meanwhile nearby water molecules are driven away from the polyplex, resulting in a less spherical liposome. Energy decomposition analyses further reveal that, at higher charge densities, the polyplex exhibits much stronger interactions with CHEMS lipids than with water molecules, with the majority contribution from electrostatic interactions. In addition, the mobility of lipids, especially CHEMS, is reduced as the polyplex charge density increases, indicating a more rigid liposome. Overall, our molecular dynamics simulations elucidate the influence of polyplex charge density on the liposome self-assembly process at the atomic level, which provides a complementary approach to experiments for a better understanding of this promising gene therapy delivery system.