Uptake and Intracellular Fate of Engineered Nanoparticles in Mammalian Cells: Capabilities and Limitations of Transmission Electron Microscopy—Polymer‐Based Nanoparticles

In order to elucidate mechanisms of nanoparticle (NP)-cell interactions, a detailed knowledge about membrane-particle interactions, intracellular distributions, and nucleus penetration capabilities, etc. becomes indispensable. The utilization of NPs as additives in many consumer products, as well as the increasing interest of tailor-made nanoobjects as novel therapeutic and diagnostic platforms, makes it essential to gain deeper insights about their biological effects. Transmission electron microscopy (TEM) represents an outstanding method to study the uptake and intracellular fate of NPs, since this technique provides a resolution far better than the particle size. Additionally, its capability to highlight ultrastructural details of the cellular interior as well as membrane features is unmatched by other approaches. Here, a summary is provided on studies utilizing TEM to investigate the uptake and mode-of-action of tailor-made polymer nanoparticles in mammalian cells. For this purpose, the capabilities as well as limitations of TEM investigations are discussed to provide a detailed overview on uptake studies of common nanoparticle systems supported by TEM investigations. Furthermore, methodologies that can, in particular, address low-contrast materials in electron microscopy, i.e., polymeric and polymer-modified nanoparticles, are highlighted.