Since the 1970’s, nanomaterials (NM) have had a powerful impact on biomedical applications such as imaging, diagnosis, drug delivery and targeting. This had led researchers to design a myriad of different NM classes without anticipating the complexity of their behaviors in vivo. Indeed, following exposure to biological fluids, NMs with a synthetic identity immediately acquire a new identity because thousands of blood proteins will competitively bind to NM surface leading to the formation of a protein corona. This biological identity completely changes NM properties and critically affects biological outcomes.
Among criteria defining synthetic identity, NM morphology was more recently considered as a key attribute to control in vivo behaviors. Nevertheless, knowledge and understanding of the fundamental mechanisms governing kinetics, composition and conformation of proteins adsorbed on NM with non-spherical morphology have been under-studied. In this context, the CoroNa proposal has three main objectives:
- understanding fundamental mechanisms governing kinetics, composition and conformation of protein corona on the surface of NM with specific morphology. Novel parameters such as shape, curvature radius and the sharpness of the angles of NM composed of polymers and polysaccharides will be considered for the first time,
- investigating the biological outcomes of protein corona formed on morphology-controlled NM
- the development of novel mathematical models correlating NM properties, protein corona and biological consequences.
Understanding whether NM morphology impacts protein corona and in vivo behaviours requires robust technological tools to manufacture NMs with controlled properties. Not only by handling NM morphology, but also 3D dimensions, surface properties and mechanical behaviours, because those parameters are interconnected. This strategy offers insights on the most important parameters involved in the protein corona and will allow accurate prediction of the in vivo fate of NMs leading to their rational design. However, manufacturing NMs with a simultaneous control of those parameters represents one of the most important challenges for the scientific community in the nanotechnology field. Unfortunately, available technologies have failed to address those issues.
In this context, the partners involved in this proposal developed complementary approaches based on supramolecular self-assembly, physical deformation of NMs and electron beam lithography to design morphology-controlled NMs with specific synthetic identity. After careful qualitative and quantitative characterizations of the protein corona, the parallelism between complement anaphylatoxin production and severity of physiological changes caused by the morphology-controlled NM will be investigated. Then, the impact of NM morphology on pharmacokinetics, biodistribution, cell uptake and toxicity will be studied. Finally, Gene Ontology Terms Screening and mathematical modelling will correlate NM synthetic identity, protein corona and biological consequences.
This project is timely, translational and multidisciplinary. It crosses boundaries between polymer chemistry, nanotechnology, biological evaluations and mathematical modelling. This investigation will fill a void of fundamental scientific knowledge by understanding the mechanisms governing kinetics, composition and conformation of protein corona on non-spherical NMs. Such fundamental knowledge will lead to novel applications to exploit the protein corona and opens alternative strategies for targeting specific organs or cell populations and for the treatment of severe diseases. Indeed, controlling protein adsorption by careful design of NM with specific synthetic identity which favors selective endogenous proteins will bring promising therapeutic benefits.
Madame Kawthar BOUCHEMAL (Institut Galien Paris Sud)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
IGPS Institut Galien Paris Sud
IPCM Institut Parisien de Chimie Moléculaire
C2N Benoit Forêt
Help of the ANR 439,843 euros
Beginning and duration of the scientific project: March 2022 - 48 Months