Nanoparticles are endocytosed and trafficked within cells by selecting one or more of the cell's intrinsic processing pathways. However, general rules which drive this selection have not yet been defined. Therefore, each nanoparticle has to be investigated separately to determine its endocytosis and intracellular trafficking pathways. By using cryo SXT to investigate the cellular interaction of two different nanoparticles, we have uncovered some general rules about nanoparticle interactions with cells. Our results highlight not only the importance of cryo-SXT for nanoparticle investigation in the medical field, but also demonstrate that a well-controlled analysis makes it possible to discern general rules about cell-nanoparticle interactions.