Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy
Open accessAbstract
Genome editing holds great potential for cancer treatment due to the ability to precisely inactivate or repair cancer-related genes. However, delivery of CRISPR/Cas to solid tumours for efficient cancer therapy remains challenging. Here we targeted tumour tissue mechanics via a multiplexed dendrimer lipid nanoparticle (LNP) approach involving co-delivery of focal adhesion kinase (FAK) siRNA, Cas9 mRNA and sgRNA (siFAK + CRISPR-LNPs) to enable tumour delivery and enhance gene-editing efficacy. We show that gene editing was enhanced >10-fold in tumour spheroids due to increased cellular uptake and tumour penetration of nanoparticles mediated by FAK-knockdown. siFAK + CRISPR-PD-L1-LNPs reduced extracellular matrix stiffness and efficiently disrupted PD-L1 expression by CRISPR/Cas gene editing, which significantly inhibited tumour growth and metastasis in four mouse models of cancer. Overall, we provide evidence that modulating the stiffness of tumour tissue can enhance gene editing in tumours, which offers a new strategy for synergistic LNPs and other nanoparticle systems to treat cancer using gene editing.
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Lipid nanoparticle (LNP) have been found to co-deliver Cas9 mRNA, focal adhesion kinase (FAK) siRNA, and sgRNA to improve both tumor delivery and gene editing efficacy.
“Lipid nanoparticle (LNP) have been found to co-delivery of Cas9 mRNA, focal adhesion kinase (FAK) siRNA, and sgRNA to improve both tumor delivery and gene editing efficacy.55”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [55]
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- Authors
- Zhang, D., Wang, G., Yu, X., Wei, T., Farbiak, L., Johnson, L. T., Taylor, A. M., Xu, J., Hong, Y., Zhu, H., & Siegwart, D. J.
- Affiliations
- Harold C. Simmons Comprehensive Cancer Center (US)
- The University of Texas Southwestern Medical Center (US)
- The University of Texas at Arlington (US)
- Corresponding author
- Siegwart, Daniel J.
- ORCID
- Venue
- Nature Nanotechnology
- Published
- 2022-05-12
- Volume
- 17
- Issue
- 7
- Pages
- 777-787
- ISSN
- 1748-3387 (ISSN-L)
- 1748-3395
- PMC
- PMC9931497
- OpenAlex
- W4280596283
- Cited by
- 243
- References
- 52
- Citations by year
- 2026: 35 · 2025: 77 · 2024: 56 · 2023: 62 · 2022: 13
- FWCI
- 16.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Nanotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Prevention and Research Institute of Texas (RP160157, RP190251)
- Pharmaceutical Research and Manufacturers of America Foundation (Predoctoral Fellowship in Drug Delivery)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01 CA251928, 5P30CA142543, R01 CA269787-01)
- U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (R01 EB025192-01A1)
- American Cancer Society (RSG-17-012-01)
- Welch Foundation (I-1855)
- Cystic Fibrosis Foundation (SIEGWA18XX0)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- CRISPR gene editing, extracellular matrix stiffness, focal adhesion kinase, siRNA knockdown, tumor spheroids, cancer immunotherapy, metastasis suppression
- MeSH terms
- Gene Editing, Animals, Liposomes, Neoplasms, Gene Transfer Techniques, Mice, Nanoparticles, B7-H1 Antigen, CRISPR-Cas Systems
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