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Optimization of lipid nanoparticles for gene editing of the liver via intraduodenal delivery.
Zhu, Yining; Cai, Shuting Sarah; Ma, Jingyao; Cheng, Leonardo; Wei, Christine; Aggarwal, Ataes; Toh, Wu Han; Shin, Charles; Shen, Ruochen; Kong, Jiayuan; Mao, Shuming Alan; Lao, Yeh-Hsing; Leong, Kam W; Mao, Hai-Quan.
Afiliación
  • Zhu Y; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21218, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, 212
  • Cai SS; Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA.
  • Ma J; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21218, USA; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
  • Cheng L; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21218, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, 212
  • Wei C; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21218, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, 212
  • Aggarwal A; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21218, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA; Department of Computer Science, Johns Hopkins University, Baltimore, MD, 21218, USA.
  • Toh WH; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA; Department of Computer Science, Johns Hopkins University, Baltimore, MD, 21218, USA; Department of Biology, Johns Hopkins University, Baltimore, MD, 21218, USA.
  • Shin C; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21218, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA.
  • Shen R; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21218, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, 212
  • Kong J; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21218, USA; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
  • Mao SA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21218, USA; Department of Computer Science, Johns Hopkins University, Baltimore, MD, 21218, USA.
  • Lao YH; Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA.
  • Leong KW; Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA; Department of Systems Biology, Columbia University Medical Center, New York, NY, 10032, USA. Electronic address: kam.leong@columbia.edu.
  • Mao HQ; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21218, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, 212
Biomaterials ; 308: 122559, 2024 Jul.
Article en En | MEDLINE | ID: mdl-38583366
ABSTRACT
Lipid nanoparticles (LNPs) have recently emerged as successful gene delivery platforms for a diverse array of disease treatments. Efforts to optimize their design for common administration methods such as intravenous injection, intramuscular injection, or inhalation, revolve primarily around the addition of targeting ligands or the choice of ionizable lipid. Here, we employed a multi-step screening method to optimize the type of helper lipid and component ratios in a plasmid DNA (pDNA) LNP library to efficiently deliver pDNA through intraduodenal delivery as an indicative route for oral administration. By addressing different physiological barriers in a stepwise manner, we down-selected effective LNP candidates from a library of over 1000 formulations. Beyond reporter protein expression, we assessed the efficiency in non-viral gene editing in mouse liver mediated by LNPs to knockdown PCSK9 and ANGPTL3 expression, thereby lowering low-density lipoprotein (LDL) cholesterol levels. Utilizing an all-in-one pDNA construct with Strep. pyogenes Cas9 and gRNAs, our results showcased that intraduodenal administration of selected LNPs facilitated targeted gene knockdown in the liver, resulting in a 27% reduction in the serum LDL cholesterol level. This LNP-based all-in-one pDNA-mediated gene editing strategy highlights its potential as an oral therapeutic approach for hypercholesterolemia, opening up new possibilities for DNA-based gene medicine applications.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Nanopartículas / Edición Génica / Lípidos / Hígado Límite: Animals / Humans Idioma: En Revista: Biomaterials Año: 2024 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Nanopartículas / Edición Génica / Lípidos / Hígado Límite: Animals / Humans Idioma: En Revista: Biomaterials Año: 2024 Tipo del documento: Article