4. Conclusions

In general, the research on nanoparticle cell internalization mechanism is very beneficial to improve the therapeutic efficiency of nanomaterial drug delivery systems. Both the nanoparticle and the cell membrane contain diverse chemical components and complex physical properties. Therefore, the effect of the properties of nanoparticles and cell membranes on the interaction is the hot-spot in this field. This article reviews the research on the factors affecting the internalization mechanism of nanoparticle in recent years and summarizes the positive and negative influence of multiple physical and chemical properties of nanoparticles, which will assist researchers to propose more reasonable nanoparticle design solutions:
(1) Nanoparticle size. Small size nanoparticles can smoothly penetrate cell membranes without causing significant cell membrane deformation. However, it also brings a lower number of surface ligands and a higher cell membrane bending energy barrier, thus properly increasing the nanoparticle size can increase the internalization efficiency. Hence, researchers should balance the relationship between cytotoxicity and membrane bending energy to determine the optimal size of nanoparticles.
(2) Nanoparticle shape. The asymmetrical shape (rod, ellipse, disc, etc.) nanoparticles are conducive to the penetration of cell membranes and have a special endocytosis dynamic: orientation-wrapping-reorientation. Compared with the isotropic shape (spherical, etc.) nanoparticles, this exceptional internalization kinetics results in a longer internalization time, but its conformation can be optimized to reduce the curvature of the cell membrane due to the orientation process which can also promote the wrapping of cell membranes.
(3) Nanoparticle surface properties. Hydrophobic nanoparticles can be embedded in the middle layer of the cell membrane, while hydrophilic nanoparticles can only be adsorbed on the surface. Therefore, researchers should reasonably adjust the ratio and distribution of the hydrophilic / hydrophobic surface of the nanoparticles. The density, length, and type of ligands on the nanoparticle surface will also affect the nanoparticle-cell membrane interaction mechanism, thereby changing the degree of nanoparticle encapsulation by the cell membrane. Moreover, since cancer cells usually contain a higher negative charge density, the charge distribution on the nanoparticle surface will also provide a greater driving force.
(4) Nanoparticle concentration. A high concentration of nanoparticles can form aggregates, increasing the size and adjusting the shape of the aggregates so that the nanoparticles can enter the cell together under the synergistic effect of the partner nanoparticles. Understanding the nanoparticle diffusion kinetics can support researchers in understanding the deep-depth mechanism of concentration effects.
(5) Nanoparticle elastic modulus. The nanoparticles with low elastic modulus are more difficult to internalize by cells due to additional deformation energy. However, a suitable elastic modulus can allow nanoparticles to flexibly modify their shape, thereby enhancing the cell internalization probability.