Efficient RNA drug delivery using red blood cell extracellular vesicles
Open accessAbstract
Most of the current methods for programmable RNA drug therapies are unsuitable for the clinic due to low uptake efficiency and high cytotoxicity. Extracellular vesicles (EVs) could solve these problems because they represent a natural mode of intercellular communication. However, current cellular sources for EV production are limited in availability and safety in terms of horizontal gene transfer. One potentially ideal source could be human red blood cells (RBCs). Group O-RBCs can be used as universal donors for large-scale EV production since they are readily available in blood banks and they are devoid of DNA. Here, we describe and validate a new strategy to generate large-scale amounts of RBC-derived EVs for the delivery of RNA drugs, including antisense oligonucleotides, Cas9 mRNA, and guide RNAs. RNA drug delivery with RBCEVs shows highly robust microRNA inhibition and CRISPR–Cas9 genome editing in both human cells and xenograft mouse models, with no observable cytotoxicity.
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Difficulties such as a lack of consistent and reliable methods for exosome purification and the efficient encapsulation of large mRNAs into exosomes must be addressed.
“However, difficulties such as a lack of consistent and reliable methods for exosome purification and the efficient encapsulation of large mRNAs into exosomes must be addressed.”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [92]
Electroporation can load approximately one-fifth of Cas9 mRNA into EVs derived from erythrocytes.
“Previous studies have demonstrated that electroporation can load approximately one-fifth of Cas9 mRNA into EVs derived from erythrocytes [92].”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [92]
Encapsulating large RNAs, e.g., mRNA, into exosomes is a technical challenge.
“Encapsulating large RNAs, e.g., mRNA, into exosomes is also a technical challenge [92].”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [92]
RBC-derived exosomes loading Cas9 mRNA system developed for treating acute myeloid leukemia (ALL) showed robust reduction in miR-125a and miR-125b expressions.
“The targeted delivery of Cas9 RNA showed a robust reduction in miR-125a and miR-125b expressions, well-known oncogenic miRNAs in leukemia [92].”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [92]
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- Authors
- Usman, W. M., Pham, T. C., Kwok, Y. Y., Vu, L. T., Ma, V., Peng, B., Chan, Y. S., Wei, L., Chin, S. M., Azad, A., He, A. B.-L., Leung, A. Y. H., Yang, M., Shyh-Chang, N., Cho, W. C., Shi, J., & Le, M. T. N.
- Affiliations
- City University of Hong Kong (HK)
- Queen Elizabeth Hospital (CN)
- Queen Mary Hospital (CN)
- Corresponding author
- Le, Minh T. N.
- ORCID
- Venue
- Nature Communications
- Published
- 2018-06-15
- Volume
- 9
- Issue
- 1
- Pages
- 2359-2359
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6004015
- OpenAlex
- W2808067587
- Cited by
- 663
- References
- 35
- Citations by year
- 2026: 63 · 2025: 99 · 2024: 97 · 2023: 121 · 2022: 90 · 2021: 82 · 2020: 65 · 2019: 41 · 2018: 3 · 2013: 1
- FWCI
- 16.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- CityU Scholars (submittedVersion, cc-by)
- Funders
- National Natural Science Foundation of China (81770099, 81602514, 81773246)
- Shenzhen Science and Technology Innovation
- Food and Health Bureau of the Government of the Hong Kong Special Administrative Region | Health and Medical Research Fund (9211101)
- Research Grants Council, University Grants Committee (21106616)
- City University of Hong Kong (9610343, 9667133, 7200475)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- antisense oligonucleotides, CRISPR/Cas9, guide RNA, microRNA inhibition, genome editing, xenograft mouse model, cytotoxicity
- MeSH terms
- Extracellular Vesicles, RNA, Guide, CRISPR-Cas Systems, Animals, Breast Neoplasms, Erythrocytes, Female, Humans, Mice, Nude, Neoplasm Transplantation, RNA, Oligonucleotides, Antisense, Drug Delivery Systems, Mice, SCID, MicroRNAs, Cell Line, Tumor, Mice, CRISPR-Cas Systems
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