Monodisperse Gold Nanoparticles for Life science & Material Science applications

Ask an Expert: How do gold nanoparticles enter cells? What factors determine intracellular uptake of nanoparticles?

Most biomedical applications involving nanoparticles require targeted delivery into specific cells. To develop more potent nanocarriers, it is important to understand their cellular uptake mechanisms.

While traditional small molecule drugs enter cells mainly through passive diffusion or active transport, nanomedicines are transported across the membrane via endocytosis. Endocytosis is generally classified into phagocytosis, pinocytosis and receptor-mediated endocytosis. Of the three primary endocytosis mechanisms, pinocytosis is mainly a passive mechanism of moving small liquid molecules inside the cell membrane and is not largely applicable to our nanoparticles. Most nanoparticles above ~5 nm in size are internalized into cells by either receptor-mediated endocytosis or phagocytosis.



Phagocytosis or ‘cell eating’ is the non-specific internalization of particulates. Immune cells including macrophages, neutrophils and monocytes as well as cancer cells are also known to internalize nanoparticles through phagocytosis. Relatively larger particles are more likely to use this route. But the cargo contained in the phagosomes will be destroyed by acidification and enzymolysis in the lysosomes. Therefore, to produce desired effects, nanomedicines need to bypass this route to avoid degradation.


Receptor-mediated endocytosis

If nanoparticles are coated with biomolecules (e.g. peptides, proteins, antibodies, ligands, affibodies, aptamers) specific to receptors on the surface of cells, the nanoparticles will bind to the outer membrane of the cell. If those receptors naturally induce receptor-mediated endocytosis, nanoparticles will follow and be sequestered inside the cell. Therefore, if you use targeted nanoparticles (nanoparticles conjugated with cell-specific biomolecules) then the dominant form of cellular uptake, by design, is receptor-mediated endocytosis.

In some cases (such as macrophages or certain cancer cell lines) phagocytosis may be adequate for cellular uptake of nanoparticles. However, in most cases receptor mediated endocytosis is preferred over phagocytosis.


What determines the cellular internalization route?

Depending on the size and surface charge and a few other factors, a specific cellular internalization route may be preferred over others. The following factors are believed to contribute to the entry of nanoparticles into cells and influence their final destination:

  • Size: With regard to nanoparticle sizing, the jury is still out on the most "optimal" uptake size. From what we know, this size varies from cell line to cell line but as a rule of thumb, smaller particles (< 0.5um) are taken up more readily and by receptor mediated endocytosis and larger particles usually require the phagocytotic mechanism.

    • Surface Charge: Cell membranes are negatively charged, so cationic nanoparticles may show a strong electrostatic interaction with the cells, resulting in rapid cellular entry. Positively charged nanoparticles can also escape from endosomes after internalization and exhibit perinuclear localization. Nanoparticles without any charge at physiological pH may interact with the cells via hydrophobic interactions.

      • Surface hydrophobicity: Hydrophobic nanoparticles have a higher affinity for the cell membrane than hydrophilic ones. Hydrophilic polymers used to coat nanoparticle surfaces, such as polyethylene glycol (PEG), poly (N-vinyl-2-pyrrolidone) (PVP), poly(aminoacids) and dextran can prolong the circulatory life of nanoparticles by shielding them from the immune system. But these coatings can form a ‘cloud’ that suppresses the interaction between the nanoparticles and lipid bilayer of the cellular membrane. The type of polymer on the nanoparticle surface may also contribute to the route selection.

        • Shape: Although shape is not directly related to the route of entry, the aspect ratio of nanoparticles may also influence their internalization route. However, the scientific community is divided on whether particles with higher aspect ratios are more favorable for uptake as compared to lower aspect ratios.

          • Cell type: The presence or absence of certain receptors on the cell surface can determine the endocytic pathway used for internalization.


          Need further assistance?

          Despite the growing body of literature in this area, controlling the intracellular delivery fate and localization of nanoparticles remains a major challenge. Feel free to contact us if you need additional information on the uptake of a specific category of nanoparticles.

          In addition to gold nanoparticles, NanoHybrids also develops nanocarriers that are custom designed for intracellular delivery and endosomal escape of therapeutic agents.

          If you are considering using nanoparticles for targeted drug delivery, drop us a line and we can help with particle design & formulation.


          Ask an Expert:

          Have a question for our scientists about working with gold nanoparticles? Submit your question using this quick form


          Related links:

          Ask an expert: What is the difference between citrate, CTAB, PEG & silica coatings

          Antibody conjugated gold nanoparticles 

          Ask an expert: Your questions about gold nanoparticles answered