Exosome-mediated delivery of CRISPR/Cas9 for targeting of oncogenic Kras G12D in pancreatic cancer
Open accessAbstract
CRISPR/Cas9 is a promising technology for gene editing. To date, intracellular delivery vehicles for CRISPR/Cas9 are limited by issues of immunogenicity, restricted packaging capacity, and low tolerance. Here, we report an alternative, nonviral delivery system for CRISPR/Cas9 based on engineered exosomes. We show that non-autologous exosomes can encapsulate CRISPR/Cas9 plasmid DNA via commonly available transfection reagents and can be delivered to recipient cancer cells to induce targeted gene deletion. As a proof-of-principle, we demonstrate that exosomes loaded with CRISPR/Cas9 can target the mutant Kras G12D oncogenic allele in pancreatic cancer cells to suppress proliferation and inhibit tumor growth in syngeneic subcutaneous and orthotopic models of pancreatic cancer. Exosomes may thus be a promising delivery platform for CRISPR/Cas9 gene editing for targeted therapies.
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Kalluri and co-workers disclosed that engineered exosomes could serve as natural cell-derived nanocarriers for CRISPR/Cas9.
“In 2021, Kalluri and co-workers disclosed that engineered exosomes could serve as natural cell-derived nanocarriers and be developed as an alternative, nonviral delivery system for CRISPR/Cas9.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [580]
Exosomes loaded with CRISPR/Cas9 target the mutant KRASG12D oncogenic allele in pancreatic cancer cells, suppressing cell proliferation and inhibiting tumor growth in vivo.
“They applied these exosomes, like compound (246), loaded with CRISPR/Cas9 to target the mutant KRASG12D oncogenic allele in pancreatic cancer cells, suppressing cell proliferation and inhibiting tumor growth in vivo.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [580]
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References 31 · Cited by 216
- Authors
- McAndrews, K. M., Xiao, F., Chronopoulos, A., LeBleu, V. S., Kugeratski, F. G., & Kalluri, R.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Northwestern University (US)
- Corresponding author
- Kalluri, Raghu
- ORCID
- Venue
- Life Science Alliance
- Publisher
- Life Science Alliance, LLC
- Published
- 2021-07-19
- Volume
- 4
- Issue
- 9
- Pages
- e202000875
- ISSN
- 2575-1077 (ISSN-L)
- PMC
- PMC8321670
- OpenAlex
- W3183615998
- Cited by
- 216
- References
- 31
- Citations by year
- 2026: 40 · 2025: 56 · 2024: 45 · 2023: 49 · 2022: 23 · 2021: 3
- FWCI
- 9.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Life Science Alliance (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- MD Anderson Cancer Center
- Odyssey Program and Theodore N. Law for Scientific Achievement
- Fifth Generation, Inc.
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- CRISPR/Cas9, engineered exosomes, KRAS G12D, pancreatic cancer, plasmid DNA encapsulation, targeted gene editing, tumor growth inhibition, syngeneic mouse model
- MeSH terms
- Gene Editing, Alleles, Animals, Biological Transport, Disease Models, Animal, Oncogenes, Pancreatic Neoplasms, Plasmids, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), Genes, Reporter, Gene Transfer Techniques, Gene Targeting, MAP Kinase Signaling System, Cell Line, Tumor, Cell Proliferation, Mice, Exosomes, CRISPR-Cas Systems, Allografts
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