CRISPR–Cas gene editing and messenger RNA-based protein replacement therapy hold tremendous potential to effectively treat disease-causing mutations with diverse cellular origin. However, it is currently impossible to rationally design nanoparticles that selectively target specific tissues. Here, we report a strategy termed selective organ targeting (SORT) wherein multiple classes of lipid nanoparticles are systematically engineered to exclusively edit extrahepatic tissues via addition of a supplemental SORT molecule. Lung-, spleen- and liver-targeted SORT lipid nanoparticles were designed to selectively edit therapeutically relevant cell types including epithelial cells, endothelial cells, B cells, T cells and hepatocytes. SORT is compatible with multiple gene editing techniques, including mRNA, Cas9 mRNA/single guide RNA and Cas9 ribonucleoprotein complexes, and is envisioned to aid the development of protein replacement and gene correction therapeutics in targeted tissues.
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D.J.S. acknowledges financial support from the National Institutes of Health (NIH) National Institute of Biomedical Imaging and Bioengineering (NIBIB) (grant no. R01 EB025192-01A1), the Cystic Fibrosis Foundation (CFF) (grant no. SIEGWA18XX0), the American Cancer Society (ACS) (grant no. RSG-17-012-01) and the Welch Foundation (grant no. I-1855). We acknowledge the UTSW Tissue Resource, supported in part by the National Cancer Institute (grant no. 5P30CA142543), the Moody Foundation Flow Cytometry Facility and the UTSW Proteomics Core. We thank Y. Jia, Y.-H. Lin, Y. Wei and H. Zhu for assistance with tissue processing and analyses.
D.J.S., Q.C., T.W. and the Reagents of the University of Texas System have filed patent applications on SORT and related technologies. D.J.S. is a co-founder of ReCode Therapeutics, which has licensed intellectual property from UT Southwestern.
Peer review information Nature Nanotechnology thanks Roy van der Meel and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Cheng, Q., Wei, T., Farbiak, L. et al. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing. Nat. Nanotechnol. 15, 313–320 (2020). https://doi.org/10.1038/s41565-020-0669-6
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