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

Yining Zhu, Ruochen Shen, Ivan Vuong, Rebekah A. Reynolds, Melanie J. Shears, Zhi-Cheng Yao, Yizong Hu, Won June Cho, Jiayuan Kong, Sashank K. Reddy, Sean C. Murphy () and Hai-Quan Mao ()
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Yining Zhu: Johns Hopkins University School of Medicine
Ruochen Shen: Johns Hopkins University School of Medicine
Ivan Vuong: Johns Hopkins University School of Medicine
Rebekah A. Reynolds: University of Washington
Melanie J. Shears: University of Washington
Zhi-Cheng Yao: Johns Hopkins University
Yizong Hu: Johns Hopkins University School of Medicine
Won June Cho: Johns Hopkins University
Jiayuan Kong: Johns Hopkins University School of Medicine
Sashank K. Reddy: Johns Hopkins University School of Medicine
Sean C. Murphy: University of Washington
Hai-Quan Mao: Johns Hopkins University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31993-y

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