Defense of Rebecca Churamani’s thesis (GOBS group)


Monday 22th april 2024
at 2:00 pm

Pierre et Marie Curie campus
Esclangon building
Durant amphitheater

Rebecca Churamani, a doctoral student in the GOBS group, will present her thesis entitled:

« Supramolecular assemblies of functionalized cyclodextrins as transfection vectors for messenger RNA »

in front of a jury composed of:

Pr. Mélanie Ethève-Quelquejeu, Université Paris-Cité (Rapporteur)

Dr. Gilles Guichard, Université de Bordeaux (Rapporteur)

Pr. Joanne Xie, ENS Paris-Saclay (Examiner)

Dr. Ghislaine Vantomme, Université d’Eindhoven (Examiner)

Pr. Philippe Guégan, Sorbonne Université (Examiner)

This defense is closed to public, and only authorized people can attend.

With the emergence of messenger RNA (mRNA) vaccines and the various applications of mRNA in gene therapy, it has become crucial to further develop the mRNA medical field. However, mRNA delivery via transfection remains a challenge. Viruses are known to be highly efficient supramolecular genetic material carriers. Among them, the tobacco mosaic virus whose capsid self-assembles in a cooperative manner with RNA, has inspired our group to design a cyclodextrin (CD)-based artificial virus to deliver mRNA.

Our group synthesized a cationic CD bearing an ammonium bridge functionalized by an adamantyl group on the side. It has been demonstrated that this CD is able to self-assemble into a supramolecular polymer with double or single stranded DNA (dsDNA or ssDNA) forming thin fibers where CDs surround the DNA molecules. However, with ssDNA, the fibers take longer to form allowing to track their assembly mechanism by cryo-EM. Surprisingly, a slight structural change where the adamantyl unit was placed in the center of the CD bridge, leads to a drastic change in the co-assembly architecture: nanotubes are obtained instead of fibers.

The construction of these nanotubes follows a multi-step assembly pathway that was elucidated through cryo-EM kinetic experiments. To apply this system to transfection with mRNA, a series of CD analogues was synthesized by modifying their lipophilicity and self-assembling properties. However, none of them showed transfection efficiency in vitro. To address this issue, a new generation of amphiphilic CDs self-assembling into nanoparticles with DNA or mRNA was designed and it has been shown that some of them could transfect cells with mRNA. It has been demonstrated that CDs analogues from which the self-assembling ability was removed could not transfect.

Thus, in this thesis, it has been demonstrated that controlling the morphology of these cooperative assemblies by precise modifications of the CD structure has enabled to design an innovative and promising mRNA transfection vector.

Keywords: Cyclodextrin, mRNA, supramolecular polymer, transfection, cooperativity.

Find out more about the GOBS group