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Study of the Endosomal Distribution of Polyplexes and Lipid Nanoparticles and their in-vitro Dissociation for Improved Gene Delivery

Project description

Improving gene delivery inside cells

Efficient delivery of genetic material inside cells is the cornerstone of gene therapies and mRNA-based vaccines. While viral vectors have been widely used, non-viral systems such as polyplexes and lipid nanoparticles offer safer and more flexible alternatives. However, they suffer from poor release of their cargo inside target cells. With the support of the Marie Skłodowska-Curie Actions programme, the DiPoLiGene project aims to improve the safety and efficiency of gene-based medicines by studying how these carriers behave within cells. Using advanced imaging and spectroscopy methods, researchers will investigate how pH changes and endosomal processes affect the release of genetic material. Project findings will pave the way for smarter, more effective gene delivery systems for therapeutic use.

Objective

Nucleic acid-based therapies are currently booming with the advent of mRNA vaccines formulation. Hence, gene delivery systems employing polyplexes or lipid nanoparticles (LNPs) as versatile carriers have shown great promise for therapeutic applications due to the advantages in terms of tuneable properties and biocompatibility. Key to the success of these therapies is the development of efficient and controlled delivery systems capable of transporting the genetic material into target cells, releasing it intracellularly, and minimizing cytotoxicity. However, the efficient release of genetic material from its carriers within the endosomal compartments of target cells remains a critical challenge. This project will investigate the endosomal distribution and in-vitro dissociation mechanisms of polyplexes and LNPs, aiming to provide an outstanding insight on the structure/activity relation of nucleic acids careers. Employing a combination of state-of-the-art microscopy and spectroscopy techniques such as Förster Resonance Energy Transfer (FRET), live-cell imaging, and physicochemical approaches, this research will uncover vital insights into the intracellular dynamics of these gene delivery carriers for the better understanding of endosomal escape and particles dissociation. Furthermore, we will explore the relations between pH distribution of endosomes at various maturation levels and the corresponding accumulation of particles. This research contributes valuable insights into the intracellular fate of gene delivery carriers and provides strategies to overcome endosomal entrapment. Improved understanding of endosomal distribution and in-vitro dissociation mechanisms will ultimately facilitate the development of more efficient and targeted gene delivery systems for therapeutic applications. This will bridge the gap between laboratory research and clinical applications for a diverse spectrum of diseases.

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2024-PF-01

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Coordinator

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 242 260,56
Address
RUE MICHEL ANGE 3
75794 PARIS
France

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Ile-de-France Ile-de-France Paris
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Research Organisations
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