Titanium dioxide (TiO2), as a representative of metallic oxides, is widely used as food additive to serve as coloring or antibacterial packaging fortifier. However, in recent years, the potential hazards of nano-sized TiO2 food additives to human beings is still in doubt. In this work, we systematically studied the interactions between three sizes of TiO2 particles and the cell membrane systems with confocal laser scanning microscopy. We used both giant unilamellar vesicles and human colon cancer cells to mimic actual cell membrane systems. The results demonstrate the strong effect of particle size on membrane disruption and leakage behaviors. Among the three sizes of TiO2 nanoparticles (NPs) used in this work, the TiO2 NPs with the size of 110-300 nm are safe. In contrast, NPs with the size of 10-30 nm and 50-100 nm will cause the rupture and leakage of cell membranes. These indicates that the cytotoxicity of nano-sized TiO2 particles increases with the decrease of particle sizes. In addition, it is found that the size effect of TiO2 particles further depends on the membrane charge state. Simulations were also introduced to understand the results. This study would provide a theoretical basis for the production designing and safety standard of metallic oxide food additives.