Clathrin-Mediated Endocytosis of Multiple Nanoparticles\nTends to Be Less Cooperative: A Computational Study

The\ninternalization of nanoparticles is of great significance for\ntheir biological applications. Clathrin-mediated endocytosis (CME)\nis one of the main endocytic pathways. However, there is still a lack\nof a fundamental understanding regarding the internalization of multiple\nnanoparticles via CME. Therefore, in this study, we conducted computational\ninvestigations to uncover detailed molecular mechanisms and kinetic\npathways for differently shaped nanoparticles in the presence of clathrin.\nParticular focus is given to understanding the CME of multiple-nanoparticle\nsystems. We found that unlike receptor-mediated endocytosis, multiple\nnanoparticles did not get cooperatively wrapped by the membrane but\ntended to undergo independent endocytosis in the presence of clathrin.\nTo further investigate the endocytosis mechanism, we studied the effects\nof clathrins, nanoparticle shape, nanoparticle size, nanoparticle\narrangement, and membrane surface tension. The self-assembly of clathrin\nprefers independent endocytosis for multiple nanoparticles. Besides,\nthe cooperative behavior is weak with increasing nanoparticle-shape\nanisotropy. However, when the membrane tension is reduced, the endocytosis\npathway for multiple nanoparticles is cooperative endocytosis. Moreover,\nwe found that the self-assembly of clathrins reduces the critical\nsize of nanoparticles to undergo cooperative wrapping by the cell\nmembrane. Our results provide valuable insights into the molecular\nmechanisms of multiple nanoparticles through CME and offer useful\nguidance for the design of nanoparticles as drug/gene delivery carriers.