Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing
Open accessAbstract
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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The highly modular nature of LNPs allows them to be optimized for organ- and cell type-specific delivery following systemic administration.
“Furthermore, the highly modular nature of LNPs allows them to be optimized for organ- and cell type-specific delivery following systemic administration.23–25”
From Predictive High-Throughput Platform for Dual Screening of mRNA Lipid Nanoparticle Blood–Brain Barrier Transfection and Crossing (2024) · cites this paper as [23]
Many obstacles still exist despite the rise in studies on delivery platforms, including toxicity and the precise distribution of mRNA to extrahepatic organs.
“Many obstacles still exist despite the rise in studies on delivery platforms, including toxicity and the precise distribution of mRNA to extrahepatic organs [13, 14].”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [14]
Helper phospholipids are amphiphilic lipids that support the lipid bilayer structure, help promote fusion with endosomal membranes, and determine the specificity of target organs.
“Helper phospholipids are amphiphilic lipids that support the lipid bilayer structure, help promote fusion with endosomal membranes, and determine the specificity of target organs.293,294”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [294]
Organ selectivity can be achieved by adjusting the proportions of lipid components.
“Organ selectivity can also be achieved by adjusting the proportions of lipid components, for example, to design spleen-targeted mRNA vaccines26,27 or lung-targeted genome editing delivery systems114,134.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [134]
Formulations designed for other tissues were less efficient, with up to ~15% editing in lung and ~3% in melanoma.
“However, formulations designed for other tissues were less efficient (i.e., up to ~15% in the lung and ~3% in melanoma) (5, 6).”
From CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy (2020) · cites this paper as [5]
Current delivery systems for nonliver tissues and tumors only result in relatively low gene editing percentages.
“Moreover, current delivery systems for nonliver tissues and tumors only result in relatively low gene editing percentages (5, 6).”
From CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy (2020) · cites this paper as [5]
Nonviral delivery vehicles for CRISPR components evaluated for liver-associated genetic diseases demonstrated gene editing of up to 60% in mice and rat livers and almost complete reduction of target protein in blood.
“These systems were evaluated for liver-associated genetic diseases, demonstrated gene editing of up to 60% in mice and rat livers, and almost a complete reduction of target protein in the blood.”
From CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy (2020) · cites this paper as [5]
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- Authors
- Cheng, Q., Wei, T., Farbiak, L., Johnson, L. T., Dilliard, S. A., & Siegwart, D. J.
- Affiliations
- Harold C. Simmons Comprehensive Cancer Center (US)
- Corresponding author
- Siegwart, Daniel J.
- Venue
- Nature Nanotechnology
- Published
- 2020-04-01
- Volume
- 15
- Issue
- 4
- Pages
- 313-320
- ISSN
- 1748-3387 (ISSN-L)
- 1748-3395
- PMC
- PMC7735425
- OpenAlex
- W3015140168
- Cited by
- 2,383
- References
- 53
- Citations by year
- 2026: 511 · 2025: 534 · 2024: 492 · 2023: 358 · 2022: 246 · 2021: 175 · 2020: 65
- FWCI
- 68.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Nanotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (R01 EB025192-01A1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- lipid nanoparticles, CRISPR gene editing, mRNA delivery, tissue-specific targeting, lung targeting, spleen targeting, liver targeting, Cas9 ribonucleoprotein, single guide RNA, protein replacement therapy, gene correction, nanoparticle surface modification
- MeSH terms
- Gene Editing, Animals, Organ Specificity, RNA, Messenger, Drug Delivery Systems, Mice, Nanoparticles, CRISPR-Cas Systems
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