Multi-step screening of DNA/lipid nanoparticles and co-delivery with siRNA to enhance and prolong gene expression

Multi-step screening of DNA/lipid nanoparticles and co-delivery with siRNA to enhance and prolong gene expression

Abstract Lipid nanoparticles hold great potential as an effective non-viral vector for nucleic acid-based gene therapy. Plasmid DNA delivery can result in extended transgene expression compared to mRNA-based technologies, yet there is a lack of systematic investigation into lipid nanoparticle compos...

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Bibliographic Details
Published in:Nature communications 2022-07, Vol.13 (1), p.4282-4282, Article 4282
Main Authors: Zhu, Yining, Shen, Ruochen, Vuong, Ivan, Reynolds, Rebekah A, Shears, Melanie J, Yao, Zhi-Cheng, Hu, Yizong, Cho, Won June, Kong, Jiayuan, Reddy, Sashank K, Murphy, Sean C, Mao, Hai-Quan
Format: Article
Language:eng
Subjects:
Deoxyribonucleic acid
DNA
Gene expression
Gene therapy
Gene transfer
Inflammation
Inflammatory response
Intravenous administration
Lipids
Liver
Nanoparticles
Nucleic acids
Plasmid DNA
Screening
siRNA
Transcription factors
Transgenes
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Summary:Abstract Lipid nanoparticles hold great potential as an effective non-viral vector for nucleic acid-based gene therapy. Plasmid DNA delivery can result in extended transgene expression compared to mRNA-based technologies, yet there is a lack of systematic investigation into lipid nanoparticle compositions for plasmid DNA delivery. Here, we report a multi-step screening platform to identify optimized plasmid DNA lipid nanoparticles for liver-targeted transgene expression. To achieve this, we analyze the role of different helper lipids and component ratios in plasmid DNA lipid nanoparticle-mediated gene delivery in vitro and in vivo. Compared to mRNA LNPs and in vivo-jetPEI/DNA nanoparticles, the identified plasmid DNA lipid nanoparticles successfully deliver transgenes and mediate prolonged expression in the liver following intravenous administration in mice. By addressing different physiological barriers in a stepwise manner, this screening platform can efficiently down select effective lipid nanoparticle candidates from a lipid nanoparticle library of over 1000 formulations. In addition, we substantially extend the duration of plasmid DNA nanoparticle-mediated transgene expression using a DNA/siRNA co-delivery approach that targets transcription factors regulating inflammatory response pathways. This lipid nanoparticle-based co-delivery strategy further highlights the unique advantages of an extended transgene expression profile using plasmid DNA delivery and offers new opportunities for DNA-based gene medicine applications.
ISSN:2041-1723
2041-1723