As explored in the previous blogs, nanoparticle size, shape and charge are all important in the nanoparticle penetration and internalisation, uptake, within our cells. When designing nanoparticles, these factors need to be considered and are almost always affected by nanoparticle coatings.
What are nanoparticle coatings?
Ligands are often used as a name to define molecules and ions for nanoparticle surface coatings. There are many different shapes, sizes and charges. 
Hydrodynamic size and shape, the size and shape when in suspension, can change with surface coatings. Adding coatings could create more spherical nanoparticles regarding of the core shape. 
Nanoparticle surface coatings can greatly affect the hydrodynamic nanoparticle size. 
Nanoparticle surface coatings can greatly affect the hydrodynamic nanoparticle size.
Nanoparticle coatings are often ligands, a molecule or ion, which are bound to the nanoparticle surface. Ligands can provide a range of functions from increasing the nanoparticle hydrodynamic size, the particle size in water, changing the shape which could make particles more spherical as well as charge, adding additional positive or negative surface coatings1.
Why we use nanoparticle coatings?
Surface coatings can be designed with the complimentary receptor proteins for selective targeting, increased binding efficiency and internalisation into target cells. Additionally, it should be designed to avoid non-specific uptake into health cells. 
Nanoparticle coatings can be labelled with a diagnostic marker which can be detected with external receivers outside the body. 
Nanoparticle surface coatings can affect charge depending on the ligand attached.
We used nanoparticle coatings often to avoid the immune system, enhance cell specific internalisation and cell or biomolecule capture for diagnostic labeling.
Evading the immune system is making stabilised nanoparticles that do not elicit an immune response. The nanoparticles stabilisation should be carried out before additional surface coatings are added as the stabilisation will ultimately affect the functionality and longevity of the nanoparticles action2. If the biofluid suspension causes unstable nanoparticles, the nanoparticles will unlikely survive evading the immune system. Evading the immune system is important to not create an immune response and to reduce the clearance of nanoparticles from the body by opsonisation. Opsonisation is where a xenobiotic, foreign substance, is bound to tags marking for phagocytosis, ingesting and eliminating xenobiotics3. Xenobiotics in this case are nanoparticles. Avoiding clearance from the body results in longer circulation time and in theory, the effectiveness of the nanoparticle depending on functionality.
Enhancing cell specific internalisation stops non-specific uptake into healthy and disease cells4. An example is targeting cancerous cells within our body. The specific uptake improves the effectiveness of the therapy by eliminating all the diseased cells as well as reducing side effects by not affecting our healthy cells.
Finally, nanoparticle coating can use specific cell or biomolecule capturing for diagnostic applications. Examples are bio-assays such as capturing biomarkers from cancerous cells and quantifying the result which would normally be below the levels of detection5.
Further nanoparticle coatings for specific actions such as reacting to the acidity, pH, of the suspension environment will be explored in an upcoming blog.
How do we functionalise nanoparticles?
This is advanced and will be covered in a separate blog but briefly, there are four common methods of functionalising nanoparticles…6
- Chemisorption (For example thiol groups on gold nanoparticles)
- Bi-functional linkers or mediator linkers – For example EDC / NHS chemistry
- Adapter molecules – For example streptavidin and biotin complexes
- Dative bonding (Forming a di-polar covalent bond)
Each method has positives and negatives where some may be limited to the nanoparticle “core” such as gold nanoparticle core for thiol chemistry. Generally, thiol chemistry would not be used for liposomes due to other, accessible functional linkers or adapted molecules available. All functionalisation aims to have a “linker” which makes it easy to add surface coatings in a controller manner. Some functionalisation use adapter molecules such as streptavidin and biotin. An example is a nanoparticle surface coating of streptavidin and the biotinylated ligand in suspension which bind and associate for sufficient and fast nanoparticle coating. The biotinylated coating can easily be swapped out or mixed with a ratio of other biotinylated coatings for full surface functionalisation.
What is the ideal nanoparticle surface coating?
Low density nanoparticle surface coatings can result in low binding efficiency with the target cells. This means nanoparticles do not interact, bind and internalise into the cell. 
Medium density nanoparticle surface coatings can result in optimal binding efficiency with the target cells. This means nanoparticles interact, bind and internalise the most efficiently into cells. 
High density nanoparticle surface coatings can result in poor binding efficiency with the target cells. This means nanoparticles are less likely to interact, bind and internalise into cells.
The ideal surface coating depends on the purpose of the nanoparticle. A common approach is densely coating nanoparticles as in theory it will increase the effects nanoparticle coating provides. However, this is not the case for all nanoparticle coatings such as enhancing cell specific internalisation in cancerous cells for example7. Densely coating a nanoparticle surface can lead to competitive inhibition of the cell receptors whereby too many receptors are stimulated in the proximity of the particle. This blocks the internalisation of the nanoparticle into the target cell via that receptor. There are other routes of internalisation depending on nanoparticle charge, target cell type and receptors which will be explored in an upcoming blog.
Recent developments have used pre-existing cancerous cells. Removing the internal cellular functions leaves an empty liposome, phospholipid bi-layer cell membrane, coated with specific cancer receptors and complementary proteins to the target cancerous cells. This avoids the difficulties in designing and optimising a nanoparticle surface coating by using pre-existing cell membranes8.
Conclusion
To conclude, it is very important to tailor nanoparticles for the desired applications. An example is tailoring nanoparticle coatings to the particular cell type to avoid non-specific binding to non-target cells, optimising internalisation and avoiding the immune system. This is a very basic introduction into the applications of nanoparticle coatings and why it is important to carefully design nanoparticle coatings for a specific purpose. There is much more to nanoparticle surface coatings that will be explored in upcoming blogs such as nanoparticle coatings for specific nanoparticle functions and the different types of nanoparticles internalisations.
References
- Shreffler, J. W., Pullan, J. E., Dailey, K. M., Mallik, S., & Brooks, A. E. (2019). Overcoming hurdles in nanoparticle clinical translation: The influence of experimental design and surface modification. In International Journal of Molecular Sciences (Vol. 20, Issue 23). Multidisciplinary Digital Publishing Institute (MDPI). https://doi.org/10.3390/ijms20236056
- Guerrini, L., Alvarez-Puebla, R. A., & Pazos-Perez, N. (2018). Surface Modifications of Nanoparticles for Stability in Biological Fluids. Materials 2018, Vol. 11, Page 1154, 11(7), 1154. https://doi.org/10.3390/MA11071154
- Gulati, N. M., Stewart, P. L., & Steinmetz, N. F. (2018). Bioinspired Shielding Strategies for Nanoparticle Drug Delivery Applications. In Molecular Pharmaceutics (Vol. 15, Issue 8, pp. 2900–2909). NIH Public Access. https://doi.org/10.1021/acs.molpharmaceut.8b00292
- Mitchell, M. J., Billingsley, M. M., Haley, R. M., Wechsler, M. E., Peppas, N. A., & Langer, R. (2021). Engineering precision nanoparticles for drug delivery. In Nature Reviews Drug Discovery (Vol. 20, Issue 2, pp. 101–124). Nature Publishing Group. https://doi.org/10.1038/s41573-020-0090-8
- Zhang, Y., Li, M., Gao, X., Chen, Y., & Liu, T. (2019). Nanotechnology in cancer diagnosis: Progress, challenges and opportunities. In Journal of Hematology and Oncology (Vol. 12, Issue 1, pp. 1–13). BioMed Central. https://doi.org/10.1186/s13045-019-0833-3
- Jazayeri, M. H., Amani, H., Pourfatollah, A. A., Pazoki-Toroudi, H., & Sedighimoghaddam, B. (2016). Various methods of gold nanoparticles (GNPs) conjugation to antibodies. In Sensing and Bio-Sensing Research (Vol. 9, pp. 17–22). Elsevier. https://doi.org/10.1016/j.sbsr.2016.04.002
- Sanità, G., Carrese, B., & Lamberti, A. (2020). Nanoparticle Surface Functionalization: How to Improve Biocompatibility and Cellular Internalization. In Frontiers in Molecular Biosciences (Vol. 7, p. 381). Frontiers. https://doi.org/10.3389/fmolb.2020.587012
- CanHarris, J. C., Scully, M. A., & Day, E. S. (2019). Cancer cell membrane-coated nanoparticles for cancer management. Cancers, 11(12). https://doi.org/10.3390/cancers11121836
