A schematic representation of the cellular pathway and transfection mechanisms of different lipid-nucleic acid complexes. Due to its pore-like nature, the hexagonal phase, fuses directly with the cell membrane, crossing it rapidly avoiding endocytosis, but leading to cytotoxic effects. On the other hand, both, the lamellar and the cubic phases, enter the cell mostly via endocytosis. Lamellar phase toxicity depends on membrane charge density (regime I and II) while the cubic phase endocytosis does not depend on membrane charge density and does not present cytotoxic effects (regime III). Adapted with permission [18]. Copyright 2016 Elsevier.