tThe fate of lipid-based nanovectors, used in genetic targeting inside cells, depends on their behaviorin biological media. In fact, during both in vitro and in vivo transfection, nanovectors come in contactwith proteins that compete for their surface and build the protein corona, their true biological identitywhile engaging the cell membrane. Nonetheless, after cell internalization, the efficacy of transfectionmay depend also on structural modifications that occurred under the protein cover, following interac-tion with biological fluids. Here, based on previous in vivo experiments, two widely used lipid mixtures,namely DOTAP/DOPC and DC-Chol/DOPE, were identified as paradigms to investigate the impact of theinner structure of nanovectors on the transfection efficiency, all being proficiently internalized. Theevolution of the inner structure of cationic lipoplexes and nanoparticles based on such lipid mixtures,following interaction with human plasma, could be unraveled. Particles were investigated in high dilu-tion, approaching the biosimilar conditions. Data have demonstrated that the modulation of their innerstructure depends on their lipid composition and the plasma concentration, still preserving the geneticpayload. Interestingly, protein contact induces a variety of inner structures with different pervious-ness, including reshaping into cubic phases of different porosity, sometimes observed upon interactionbetween carrier-lipids and cell-lipids. Cubic reshaping is of biological relevance, as lipid cubic phaseshave been recently associated to both fusogenicity and to the readiness in releasing the payload to thefinal target via endosomal escape.