[en] Lipid-based nanocarriers such as liposomes or lipid nanoparticles (LNPs) have demonstrated high interest in delivering genetic material. This has been recently emphasized by the approval of Onpattro® and COVID-19 vaccines. PEGylation is known to provide lipid-based nanocarriers with stealth properties, but it also leads to reduced cellular uptake and endosomal escape, and to the production of anti-PEG antibodies causing accelerated blood clearance (ABC) and hypersensitivity reactions (HSR). This work highlights the great potential of amphiphilic poly(N-methyl-N-vinylacetamide) (PNMVA) derivatives as alternatives to lipid-PEG for post-insertion into lipoplexes and pre-insertion into LNPs designed for siRNA delivery. PNMVA compounds with different degrees of polymerization and hydrophobic segments, such as octadecyl and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), were synthesized. Among them, DSPE-PNMVA efficiently integrated into lipoplex and LNP membranes and prevented protein corona formation around these lipid carriers, exhibiting stealth properties comparable to DSPE-PEG. However, unlike DSPE-PEG, DSPE-PNMVA24 showed no adverse impact on lipoplexes cell uptake and endosomal escape. In in vivo study with mice, DSPE-PNMVA24 lipoplexes demonstrated no liver accumulation, indicating good stealth properties, extended circulation time after a second dose, reduced immunological reaction, and no systemic pro-inflammatory response. Safety of DSPE-PNMVA24 was confirmed at the cellular level and in animal models of zebrafish and mice. Overall, DSPE-PNMVA is an advantageous substitute to DSPE-PEG for siRNA delivery, offering comparable stealth and toxicity properties while improving efficacy of the lipid-based carriers by minimizing the dilemma effect and reducing immunological reactions, meaning no ABC or HSR effects.
Research center :
CESAM - Complex and Entangled Systems from Atoms to Materials - ULiège [BE] CERM - Center for Education and Research on Macromolecules - ULiège [BE] CIRM - Centre Interdisciplinaire de Recherche sur le Médicament - ULiège [BE] GIGA - Cancer - ULiège [BE] GIGA - Molecular Biology of Diseases - ULiège [BE] GIGA - Platform Zebrafish Facility & Transgenics - ULiège [ BE ]
Berger, Manon ✱; University of Liège [ULiège] - Center for Interdisciplinary Research on Medicines [CIRM] - Laboratory of Pharmaceutical Technology and Biopharmacy - Belgium
Toussaint, François ✱; University of Liège [ULiège] - Complex and Entangled Systems from Atoms to Materials [CESAM] - Research Unit, Center for Education and Research on Macromolecules [CERM] - Belgium
Djemaa, Sanaa Ben ✱; University of Liège [ULiège] - GIGA-Molecular Biology of Diseases - Laboratory of Gene Expression and Cancer [GEC] - Belgium
Maquoi, Erik ; University of Liège [ULiège] - GIGA-Cancer - Laboratory of Tumor and Development Biology - Belgium
Pendeville-Samain, Hélène ; University of Liège [ULiège] - GIGA - Platform Zebrafish Facility and Transgenics - Belgium
Evrard, Brigitte ; University of Liège [ULiège] - Center for Interdisciplinary Research on Medicines [CIRM] - Laboratory of Pharmaceutical Technology and Biopharmacy - Belgium
Jérôme, Christine ; University of Liège [ULiège] - Complex and Entangled Systems from Atoms to Materials [CESAM] - Research Unit, Center for Education and Research on Macromolecules [CERM] - Belgium
Chain, Jeanne Leblond; University of Bordeaux - Centre National de la Recherche Scientifique [CNRS] - Institut national de la santé et de la recherche médicale [INSERM] - Laboratory " Acides nucléiques : Régulations naturelles et artificielles [ARNA] " - France
Lechanteur, Anna ; University of Liège [ULiège] - Center for Interdisciplinary Research on Medicines [CIRM] - Laboratory of Pharmaceutical Technology and Biopharmacy - Belgium
Mottet, Denis ✱; University of Liège [ULiège] - GIGA-Molecular Biology of Diseases - Laboratory of Gene Expression and Cancer [GEC] - Belgium
Debuigne, Antoine ✱; University of Liège [ULiège] - Complex and Entangled Systems from Atoms to Materials [CESAM] - Research Unit, Center for Education and Research on Macromolecules [CERM] - Belgium
Piel, Géraldine ✱; University of Liège [ULiège] - Center for Interdisciplinary Research on Medicines [CIRM] - Laboratory of Pharmaceutical Technology and Biopharmacy - Belgium
✱ These authors have contributed equally to this work.
Language :
English
Title :
Poly(N-methyl‐N‐vinylacetamide): a strong alternative to PEG for lipid‐based nanocarriers delivering siRNA
Publication date :
23 November 2023
Journal title :
Advanced Healthcare Materials
ISSN :
2192-2640
eISSN :
2192-2659
Publisher :
Wiley, Germany
Pages :
e2302712
Peer reviewed :
Peer Reviewed verified by ORBi
Name of the research project :
The "LIPEGALT" project
Funders :
F.R.S.-FNRS - Fund for Scientific Research [BE] Actions de Recherche Concertées [ARC] - ULiège [BE] Walloon region [BE]
Funding text :
The research was supported by the Wallonia-Brussels Federation (grant for Concerted Research Actions, LIPEGALT project, ULiège). Authors would like to thank Luc Duwez and Olivier Nivelles (GIGA-Mouse facility, University of Liege) for their help in mice experiments. Our data of flow cytometry and toxicity in Zebrafish were obtained with the assistance of the GIGA-Flow Cytometry and GIGA-Zebrafish facilities of the University of Liege. A.D. and DM are FNRS Senior Research Associate. They thank FNRS for financial support.
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