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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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“In another case, CRISPR/Cas9 technology has been loaded into synthetic exosomes to specifically target cancerous cells for gene editing, offering a potential new approach to treating genetic disorders and certain types of cancers [45].”
From Emerging role of exosomes in cancer therapy: progress and challenges (2025) · cites this paper as [45]
In the citing paper
“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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BackgroundExosomes as smart drug delivery vehicles for cancer immunotherapy
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“, 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. (2024) · International Journal of Nanomedicine · doi:10.2147/ijn.s464249 · Cited by 121
“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
“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
Osteikoetxea, X., da Silva, A. M., Lázaro‐Ibáñez, E., Salmond, N., Shatnyeva, O., Stein, J., Schick, J., Wren, S. A. C., Lindgren, J., Firth, M. A., et al. (2022) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12225 · Cited by 118
“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 113
Li, J., Zhang, Y., Dong, P.-Y., Yang, G.-M., & Gurunathan, S. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115087 · Cited by 115
The Therapeutic Potential and Clinical Significance of Exosomes as Carriers of Drug Delivery System
Li, T., Li, X., Han, G., Liang, M., Yang, Z., Zhang, C., Huang, S., Tai, S., & Yu, S. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics15010021 · Cited by 110
“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
Chen, R., Huang, H., Liu, H., Xi, J., Ning, J., Zeng, W., Shen, C., Zhang, T., Yu, G., Xu, Q., et al. (2019) · Small · doi:10.1002/smll.201902686 · Cited by 109
Trends in Research on Exosomes in Cancer Progression and Anticancer Therapy
Sinha, D., Roy, S., Saha, P., Chatterjee, N., & Bishayee, A. (2021) · Cancers · doi:10.3390/cancers13020326 · Cited by 110
Engineered extracellular vesicles as intelligent nanosystems for next-generation nanomedicine
Fan, Z., Jiang, C., Wang, Y., Wang, K., Marsh, J., Zhang, D., Chen, X., & Nie, L. (2022) · Nanoscale Horizons · doi:10.1039/d2nh00070a · Cited by 103
Mashel, T. V., Tarakanchikova, Y. V., Muslimov, A. R., Zyuzin, M. V., Timin, A. S., Lepik, K. V., & Fehse, B. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.120282 · Cited by 102
Suwatthanarak, T., Thiodorus, I. A., Tanaka, M., Shimada, T., Takeshita, D., Yasui, T., Baba, Y., & Okochi, M. (2020) · Lab on a Chip · doi:10.1039/d0lc00899k · Cited by 101
Chen, Y., Douanne, N., Wu, T.-C., Kaur, I., Tsering, T., Erzingatzian, A., Nadeau, A., Juncker, D., Nerguizian, V., & Burnier, J. V. (2025) · Science Advances · doi:10.1126/sciadv.ads5249 · Cited by 107
Extracellular vesicles in cancer nanomedicine
Tarasov, V. V., Svistunov, A. A., Chubarev, V. N., Dostdar, S. A., Sokolov, A. V., Brzecka, A., Sukocheva, O., Neganova, M. E., Klochkov, S. G., Somasundaram, S. G., et al. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.08.017 · Cited by 97
The roles of exosomes in cancer drug resistance and its therapeutic application
Li, S., Yi, M., Dong, B., Jiao, Y., Luo, S., & Wu, K. (2020) · Clinical and Translational Medicine · doi:10.1002/ctm2.257 · Cited by 99
Wang, Z., Mo, H., He, Z., Chen, A., & Cheng, P. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113480 · Cited by 100
CRISPR/Cas9 Delivery System Engineering for Genome Editing in Therapeutic Applications
Cheng, H., Zhang, F., & Ding, Y. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13101649 · Cited by 100
Advances in Extracellular Vesicle Nanotechnology for Precision Theranostics
Wu, Q., Fu, S., Xiao, H., Du, J., Cheng, F., Wan, S., Zhu, H., Li, D., Peng, F., Ding, X., et al. (2022) · Advanced Science · doi:10.1002/advs.202204814 · Cited by 97
Clinical relevance of extracellular vesicles in cancer — therapeutic and diagnostic potential
Greening, D. W., Xu, R., Rai, A., Suwakulsiri, W., Chen, M., & Simpson, R. J. (2025) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-025-01074-2 · Cited by 129
Stem Cell-Derived Exosome in Cardiovascular Diseases: Macro Roles of Micro Particles
Yuan, Y., Du, W., Liu, J., Ma, W., Zhang, L., Du, Z., & Cai, B. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00547 · Cited by 95
Ahmadi, S. E., Soleymani, M., Shahriyary, F., Amirzargar, M. R., Mahya, O., Fattahi, D., & Safa, M. (2023) · Cancer Gene Therapy · doi:10.1038/s41417-023-00597-z · Cited by 97
“The combination of both therapeutic approaches resulted in 57% inhibition of cancer proliferation, almost twice the effect of exosomes- or cisplatin-sole treatment [118].”
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Xu, L., Faruqu, F. N., Liam‐Or, R., Abed, O. S. A., Li, D., Venner, K., Errington, R. J., Summers, H. D., Wang, J. T.-W., & Al‐Jamal, K. T. (2020) · Journal of Extracellular Vesicles · doi:10.1080/20013078.2020.1779458 · Cited by 97
“This suggests that PC cells show cell-specific preference towards internalising self-exosomes, which was also observed in other contexts such as in ovarian cancer models [19].”
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Biomaterials as vectors for the delivery of CRISPR–Cas9
Eoh, J. H., & Gu, L. (2019) · Biomaterials Science · doi:10.1039/c8bm01310a · Cited by 92
Microfluidic on-demand engineering of exosomes towards cancer immunotherapy
Zhao, Z., McGill, J. L., Kubota, P. G., & He, M. (2019) · Lab on a Chip · doi:10.1039/c8lc01279b · Cited by 89
Blood TfR+ exosomes separated by a pH-responsive method deliver chemotherapeutics for tumor therapy
Yang, L., Han, D., Zhan, Q., Li, X., Shan, P., Hu, Y., Ding, H., Wang, Y., Zhang, L., Zhang, Y., et al. (2019) · Theranostics · doi:10.7150/thno.37220 · Cited by 90
“The state-of-art CRISPR/Cas9 system has also been successfully transported through exosomes recently [11,12].”
BackgroundApplication of the CRISPR/Cas9 System to Drug Resistance in Breast Cancer
Chen, Y., & Zhang, Y. (2018) · Advanced Science · doi:10.1002/advs.201700964 · Cited by 91
Metadata
- 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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