Contributors: Institut des Sciences Chimiques de Rennes (ISCR); Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes); Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS); Universidad de Guadalajara; Centre de Recherche Paul Pascal (CRPP); Université de Bordeaux (UB)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS); Nutrition, Métabolismes et Cancer (NuMeCan); Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE); SynNanoVect; Université de Brest (UBO)-IFR148 ScInBioS; Université de Brest (UBO); Ecole Nationale Supérieure de Chimie de Rennes (ENSCR); Team 3 LCPO : Polymer Self-Assembly & Life Sciences; Laboratoire de Chimie des Polymères Organiques (LCPO); Université de Bordeaux (UB)-École Nationale Supérieure de Chimie, de Biologie et de Physique (ENSCBP)-Institut Polytechnique de Bordeaux-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-École Nationale Supérieure de Chimie, de Biologie et de Physique (ENSCBP)-Institut Polytechnique de Bordeaux-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS); Lourdes Mónica Bravo-Anaya acknowledges the French National Agency of Research (ANR) for the grant (ANR-21-CE06-0027-01), the IEA P2NanoBio founded by the CNRS, as well as the AES 2021 and the AIS Allocation 2023 founded by Rennes Métropole.; ANR-21-CE06-0027,DIMECO,Mécanismes de désassemblage de complexes contenant des acides nucléiques pour le relargage de gènes(2021)
Abstract: International audience ; The lack of understanding of polyplexes stability and their dissociation mechanisms, allowing the release of DNA, is currently a major limitation in non-viral gene delivery. One proposed mechanism for DNA-based polyplexes dissociation is based on the electrostatic interactions between polycations and biological polyanions, such as glycosaminoglycans (GAGs). This work aimed at investigating whether GAGs such as heparin, chondroitin sulphate and hyaluronic acid promote the dissociation of PEI/DNA polyplexes. We studied the electrostatic complexation between branched poly(ethyleneimine) (b-PEI25) and polyanions (model DNA and GAGs) through conductivity and ζ-potential measurements. The formation of b-PEI25/polyanion polyplexes through electrostatic interactions was analyzed in depth, providing key insights into charge stoichiometry, morphology, thermodynamics and physicochemical characteristics. The stability of polyplexes was tested in the presence of the different GAGs. Heparin was found to be the only polyanion capable of releasing peGFP-C3 plasmid from polyplexes, complexing stoichiometrically with the free b-PEI25 in excess, before releasing the plasmid. The ability of GAGs to disrupt polyplexes and release DNA was correlated with the thermodynamic characteristics of b-PEI25/polyanions complexation. Our findings indicate that heparin's strong interaction with PEI and its high charge density, compared to other GAGs and polyanions, are pivotal in determining complex stability and promoting DNA release.
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