Description

Autoimmune hepatitis is a chronic inflammatory liver disease currently treated with nonspecific immunosuppressive drugs, which are associated with substantial adverse effects and frequent relapses. This PhD project, conducted within the ANR-funded MAGNETIMA project, aims to develop multifunctional magnetic nanoassemblies combining iron oxide nanoparticles, an anti-inflammatory or immunosuppressive drug, and an antigenic peptide designed to promote antigen-specific immune tolerance.

Nanoassemblies with a hydrodynamic diameter of 50–60 nm will be prepared by flash nanoprecipitation and characterized to establish relationships between their composition, structural organization, stability, biodegradation, magnetic properties, and drug-release kinetics. The magnetic-core composition and alternating magnetic field parameters will be optimized to achieve controlled drug release under conditions compatible with biological environments.

Magnetic Particle Imaging (MPI) will be used to quantify the nanoassemblies, detect changes associated with their disassembly or degradation, and monitor their pharmacokinetics and biodistribution. The selected formulations will subsequently be evaluated by the consortium partners using human macrophage models, three-dimensional hepatic models, and a murine model of autoimmune hepatitis.

The main challenge is to overcome the limitations of systemic immunosuppression by developing a strategy that acts locally in the liver and combines two complementary mechanisms: anti-inflammatory activity triggered by an alternating magnetic field and the induction of antigen-specific immune tolerance.

Several scientific and technological barriers will need to be addressed. The project must produce 50–60 nm nanoassemblies that are sufficiently stable in biological environments while retaining the ability to disassemble in a controlled manner. It must also achieve reproducible magnetically triggered drug release, control the density and integrity of the antigenic peptide, and relate the physicochemical transformations of the nanoassemblies to their biological fate and immunological effects.

A major methodological challenge will be to determine whether MPI can provide information not only on the amount and localization of iron oxide nanoparticles, but also on their assembly state, degradation, and drug-release process. Ultimately, the project aims to provide preclinical proof of concept for precision magnetic immunomodulation in autoimmune hepatitis, with potential applications to other immune-mediated diseases.