Cancer-derived exosomes as a delivery platform of CRISPR/Cas9 confer cancer cell tropism-dependent targeting
Abstract
An intracellular delivery system for CRISPR/Cas9 is crucial for its application as a therapeutic genome editing technology in a broad range of diseases. Current vehicles carrying CRISPR/Cas9 limit in vivo delivery because of low tolerance and immunogenicity; thus, the in vivo delivery of genome editing remains challenging. Here, we report that cancer-derived exosomes function as natural carriers that can efficiently deliver CRISPR/Cas9 plasmids to cancer. Compared to epithelial cell-derived exosomes, cancer-derived exosomes provide potential vehicles for effective in vivo delivery via selective accumulation in ovarian cancer tumors of SKOV3 xenograft mice, most likely because of their cell tropism. CRISPR/Cas9-loaded exosomes can suppress expression of poly (ADP-ribose) polymerase-1 (PARP-1), resulting in the induction of apoptosis in ovarian cancer. Furthermore, the inhibition of PARP-1 by CRISPR/Cas9-mediated genome editing enhances the chemosensitivity to cisplatin, showing synergistic cytotoxicity. Based on these results, tumor-derived exosomes may be very promising for cancer therapeutics in the future.
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CRISPR/Cas9-loaded exosomes from SKOV3 significantly down-regulated PARP-1 expression, causing ovarian cancer cell death.
“The CRISPR/Cas9-loaded exosomes significantly down-regulated PARP-1 expression, thus causing ovarian cancer cell death [54].”
From The Therapeutic Potential and Clinical Significance of Exosomes as Carriers of Drug Delivery System (2022) · cites this paper as [54]
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“These sEVs accumulated more in the SKOV3 cell line to a larger extent (136).”
Extracellular vesicles: Emerging tools as therapeutic agent carriers
Liu, S., Wu, X., Chandra, S., Lyon, C. J., Ning, B., Jiang, L., Fan, J., & Hu, Y. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.05.002 · Cited by 146 · see citing works
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Exosome for mRNA delivery: Strategies and therapeutic applications
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The next-generation DNA vaccine platforms and delivery systems: advances, challenges and prospects
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Non-viral delivery of the CRISPR/Cas system: DNA versus RNA versus RNP
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Exploiting Exosomes in Cancer Liquid Biopsies and Drug Delivery
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Gesicle-Mediated Delivery of CRISPR/Cas9 Ribonucleoprotein Complex for Inactivating the HIV Provirus
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Clinical applications for exosomes: Are we there yet?
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“CRISPR-Cas systems can also be delivered using exosomes instead of viral vectors where safety and logistical challenges to package such large cargoes have created limi- tations for wider use (Kim et al., 2017; Knott & Doudna, 2018).”
BackgroundDelivery of cancer therapies by synthetic and bio-inspired nanovectors
Briolay, T., Petithomme, T., Fouet, M., Nguyen-Pham, N., Blanquart, C., & Boisgerault, N. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01346-2 · Cited by 131 · see citing works
Extracellular Vesicles as Natural, Safe and Efficient Drug Delivery Systems
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“This innovative EV-based approach has proved to be effective, being able to inhibit ovarian cancer proliferation by activating an apoptotic pathway in SKOV3-derived tumors in mice [43].”
BackgroundLi, M., Xie, H., Liu, Y., Xia, C., Cun, X., Long, Y., Chen, X., Deng, M., Guo, R., Zhang, Z., et al. (2019) · Journal of Controlled Release · doi:10.1016/j.jconrel.2019.05.019 · Cited by 127 · see citing works
CRISPR/Cas9 systems: Delivery technologies and biomedical applications
Du, Y., Liu, Y., Hu, J., Peng, X., & Liu, Z. (2023) · Asian Journal of Pharmaceutical Sciences · doi:10.1016/j.ajps.2023.100854 · Cited by 135 · see citing works
“It has been observed that exosomes derived from tumor cells exhibit minimal immunogenicity and toxicity, making them suitable natural carriers for delivering CRISPR/Cas9 to tumor cells for gene editing purposes [98 ,99] .”
BackgroundZhang, C., Qin, C., Dewanjee, S., Bhattacharya, H., Chakraborty, P., Jha, N. K., Gangopadhyay, M., Jha, S. K., & Liu, Q. (2024) · Molecular Cancer · doi:10.1186/s12943-024-01932-0 · Cited by 133 · see citing works
“The ensuing synergistic cytotoxic effects underscore the potential of exosomes as a promising avenue for tumor therapy [275].”
BackgroundCRISPR/Cas9: Principle, Applications, and Delivery through Extracellular Vesicles
Horodecka, K., & Düchler, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22116072 · Cited by 130 · see citing works
“While SKOV3-Exo accumulated at the tumor sites, HEK293-Exo were also found in other tissues including the liver, which is a common off-target site of accumulation [98].”
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Viral and Non-Viral Systems to Deliver Gene Therapeutics to Clinical Targets
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“This highlights the potential of these exosomes in cancer therapeutics [105].”
BackgroundEngineering therapeutical extracellular vesicles for clinical translation
Ma, Y., Dong, S., Grippin, A., Teng, L., Lee, A. S., Kim, B. Y. S., & Jiang, W. (2024) · Trends in biotechnology · doi:10.1016/j.tibtech.2024.08.007 · Cited by 126 · see citing works
Nucleic acid delivery with extracellular vesicles
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Nanomedicine to target multidrug resistant tumors
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“This approach allowed us to determine relevant parameters, such the number of AuNPs per EV, the number of EVs internalized per cell and the number of EVs in tumor tissue, which has been mostly reported as non-quantitative fluorescent intensity units or % of internalization [7, 12, 13, 54].”
BackgroundMethodResultInfluentialExosomes as drug delivery vehicle and contributor of resistance to anticancer drugs
Chinnappan, M., Srivastava, A., Amreddy, N., Razaq, M., Pareek, V., Ahmed, R. A., Mehta, M., Peterson, J. E. G., Munshi, A., & Ramesh, R. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.05.004 · Cited by 116 · see citing works
“Such ligand/ antibody displaying exosomes were reported to function effectively in suppressing tumor growth since they are taken up by recipient tumor cells through a receptor mediated endocytosis process that avoids endosome encapsulation and trapping [54].”
BackgroundExosomes as smart drug delivery vehicles for cancer immunotherapy
Zhang, H., Wang, S., Sun, M., Cui, Y., Xing, J., Teng, L., Xi, Z., & Yang, Z. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1093607 · Cited by 118 · see citing works
“, red blood cells (25), platelets (26), immune cells (27), fibroblasts (28), endothelial cells (29), epithelial cells (30) and tumor cells (31).”
BackgroundBahadorani, M., Nasiri, M., Dellinger, K., Aravamudhan, S., & Zadegan, R. M. (2024) · International Journal of Nanomedicine · doi:10.2147/ijn.s464249 · Cited by 125 · see citing works
“89 In another study, exosomes from red blood cells served as carriers for the mRNA form of CRISPR Cas9, demonstrating greater efficiency compared to plasmid form in breast cancer cells and leukemia, both in vivo and in vitro.”
BackgroundNon-Viral Delivery To Enable Genome Editing
Rui, Y., Wilson, D. R., & Green, J. J. (2018) · Trends in biotechnology · doi:10.1016/j.tibtech.2018.08.010 · Cited by 115 · see citing works
“Using biologically derived materials, Kim and colleagues used cancer-derived exosomes as the delivery vehicle for plasmid DNA encoding a CRISPR/Cas system and showed efficient and targeted editing in an ovarian cancer model [64].”
MethodEngineered Cas9 extracellular vesicles as a novel gene editing tool
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“In terms of delivery of Cas9 by EVs there are other studies confirming this to be possible (Chen et al., 2019; Kim et al., 2017; Lin et al., 2018, Montagna et al., 2018; Ye et al., 2020).”
BackgroundMethodStrategies to overcome the main challenges of the use of exosomes as drug carrier for cancer therapy
Hussen, B. M., Faraj, G. S. H., Rasul, M. F., Hidayat, H. J., Salihi, A. B., Baniahmad, A., Taheri, M. N., & Ghafouri‐Fard, S. (2022) · Cancer Cell International · doi:10.1186/s12935-022-02743-3 · Cited by 110 · see citing works
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The Therapeutic Potential and Clinical Significance of Exosomes as Carriers of Drug Delivery System
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“The CRISPR/Cas9loaded exosomes significantly down-regulated PARP-1 expression, thus causing ovarian cancer cell death [54].”
BackgroundFriend or Foe? Evidence Indicates Endogenous Exosomes Can Deliver Functional gRNA and Cas9 Protein
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Trends in Research on Exosomes in Cancer Progression and Anticancer Therapy
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Engineered extracellular vesicles as intelligent nanosystems for next-generation nanomedicine
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CRISPR/Cas9 Delivery System Engineering for Genome Editing in Therapeutic Applications
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Advances in Extracellular Vesicle Nanotechnology for Precision Theranostics
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Blood TfR+ exosomes separated by a pH-responsive method deliver chemotherapeutics for tumor therapy
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- Authors
- Kim, S. M., Yang, Y., Oh, S. J., Hong, Y., Seo, M., & Jang, M.
- Affiliations
- Korea Institute of Science and Technology (KR)
- Korea University (KR)
- Corresponding author
- Jang, Mihue
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 266
- Pages
- 8-16
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W2754835295
- Cited by
- 481
- References
- 39
- Citations by year
- 2026: 43 · 2025: 62 · 2024: 61 · 2023: 70 · 2022: 74 · 2021: 59 · 2020: 57 · 2019: 37 · 2018: 17 · 2017: 1
- FWCI
- 12.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Funders
- KIST (2E26910)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- tumor-derived exosomes, CRISPR/Cas9 delivery, ovarian cancer, apoptosis, cisplatin sensitivity, genome editing
- MeSH terms
- Poly (ADP-Ribose) Polymerase-1, Animals, Antineoplastic Agents, Cisplatin, Combined Modality Therapy, Female, Humans, Leukocytes, Mononuclear, Mice, Inbred BALB C, Mice, Nude, Neoplasms, RNA, Genetic Therapy, Cytokines, Gene Transfer Techniques, Cell Line, Tumor, Exosomes, HEK293 Cells, CRISPR-Cas Systems
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