Nucleic acid-mediated tuning of charge: A strategy to dampen the immunotoxic effect of cationic lipid nanocarriers

Arindam K Dey (1,2)*, Adrien Nougarede (1,3), Flora Clément (1,2,4), Carole Fournier (1,2), Evelyne Jouvin-Marche (1,2), Marie Escudé (1,3), Dorothée Jary (1,3), Fabrice P. Navarro (1,3) and Patrice N Marche (1,2)

1) Université Grenoble-Alpes, 38400 St Martin d’Heres, France
2) Institute for Advanced Biosciences, Research Center INSERM U1209, CNRS UMR5309, 38700 La Tronche, France
3) CEA, LETI, Division for biology and healthcare technologies, Microfluidic Systems and Bioengineering Lab, 38000 Grenoble, France
4) CEA, INSERM, IRIG-BIOMICS, 38000, Grenoble, France

Nanotechnology has the ability to improve gene therapy by delivering therapeutic nucleic acids. Lipid nanoparticles currently in use for several biomedical applications integrate cationic lipids as carriers to form complexes. An increased surface area to volume ratio and charge of nanocarriers facilitate their interaction with target cells, but this may also lead to undesired effects. By influencing immune parameters in the host, such as phagocytes, which engulf foreign materials, carriers may cause side effects. Therefore, monitoring phagocyte functions aids in immunotoxicity screening.
We examined the roles of non-activated and LPS or IL-4-activated primary bone marrow-derived macrophages (BMDMs), as representative of M1 and M2 macrophages, in response to cationic lipid carriers (cNLCs) (45.18 nm; +45.8 mV). We monitored the effects of cNLCs on BMDMs by assessing pro-inflammatory molecules, including IL-6, TNF-a, MCP-1, Nitric Oxide (NO), and metabolism (glycolysis and oxidative phosphorylation). Our results showed that cNLCs remarkably enhanced the secretion of several molecules (IL-6, TNF-a, MCP-1, NO) as well as the metabolism in non-activated and LPS- or IL-4-activated BMDMs. In order to tune the positive charge of cNLCs, we combined them with negatively charged RNA at different N/P ratios between positively-charged amine groups of cNLCs (N = nitrogen) and negatively-charged phosphate (P) groups of nucleic acid (N/P=8/4/2/1). Our results demonstrate that reversing the surface charge of cationic lipid nanocarriers with an oppositely charged biomaterial, such as RNA, can minimize the immunostimulatory activities of the cationic nanocarrier.
We conclude that the surface charge of cationic lipid alters the fate and response of immune cells. Reversing the surface charge of cationic lipids with biomaterial, such as nucleic acid, can dampen inflammatory activities of the cationic nanocarrier.
This project has received funding from the European Union’s Horizon 2020 research and innovation program H2020 “NEWDEAL” (grant agreement No. 720905).



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