A Versatile Nonviral Delivery System for Multiplex Gene-Editing in the Liver
| Autor: | Hanze Hu, Tzu-Chieh Ho, Dantong Huang, Kam W. Leong, Hong-Xia Wang, Yeh-Hsing Lao, Jing Gong, Naazanene Vatan, Dan Shao, Jonathan Guo, Mingqiang Li |
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| Rok vydání: | 2020 |
| Předmět: |
Materials science
Genetic enhancement 02 engineering and technology 010402 general chemistry 01 natural sciences Article Genome editing CRISPR Humans General Materials Science Multiplex Guide RNA Gene Angiopoietin-Like Protein 3 Gene Editing Drug Carriers Cas9 Mechanical Engineering Gene Transfer Techniques 021001 nanoscience & nanotechnology Lipids 0104 chemical sciences Cell biology Angiopoietin-like Proteins Liver Mechanics of Materials Lipofectamine Nanoparticles CRISPR-Cas Systems Proprotein Convertase 9 0210 nano-technology |
| Zdroj: | Adv Mater |
| ISSN: | 1521-4095 |
| Popis: | Recent advances in CRISPR present attractive genome-editing toolsets to implement therapeutic strategies at the genetic level. Here, we report a liposome-coated mesoporous silica nanoparticle (lipoMSN) as an effective CRISPR delivery system for multiplex gene-editing in the liver. The use of MSN provides a large surface area for efficient loading of the large Cas9 plasmid as well as Cas9 protein/guide RNA ribonucleoprotein complex (RNP), while liposome coating offers improved serum stability and enhanced cell uptake. Hypothesizing that a loss-of-function mutation in the lipid metabolism-related pcsk9, apoc3, and angptl3 genes would improve cardiovascular health by lowering blood cholesterol and triglycerides, we used this lipoMSN platform to deliver a combination of RNPs targeting three genes.([1]) When targeting a single gene, the lipoMSN achieved a 54% gene editing efficiency, higher than the state-of-art Lipofectamine CRISPRMax. In the multiplex scenario, the lipoMSN maintained significant gene editing at each gene target despite reduced dosage of target-specific RNP. By delivering combinations of targeting RNPs in the same nanoparticle, synergistic effects on lipid metabolism were observed both in vitro and in vivo. These effects, such as a 50% decrease in serum cholesterol 4-weeks post-treatment with lipoMSN carrying both pcsk9- and angptl3- targeted RNPs, could not be reached with a single gene-editing approach. Taken together, this lipoMSN represents a versatile platform for the development of efficient, combinatorial gene editing therapeutics. |
| Databáze: | OpenAIRE |
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