The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation
Open accessAbstract
Exosomes are attractive as nucleic-acid carriers because of their favourable pharmacokinetic and immunological properties and their ability to penetrate physiological barriers that are impermeable to synthetic drug-delivery vehicles. However, inserting exogenous nucleic acids, especially large messenger RNAs, into cell-secreted exosomes leads to low yields. Here we report a cellular-nanoporation method for the production of large quantities of exosomes containing therapeutic mRNAs and targeting peptides. We transfected various source cells with plasmid DNAs and stimulated the cells with a focal and transient electrical stimulus that promotes the release of exosomes carrying transcribed mRNAs and targeting peptides. Compared with bulk electroporation and other exosome-production strategies, cellular nanoporation produced up to 50-fold more exosomes and a more than 10 3-fold increase in exosomal mRNA transcripts, even from cells with low basal levels of exosome secretion. In orthotopic phosphatase and tensin homologue (PTEN)-deficient glioma mouse models, mRNA-containing exosomes restored tumour-suppressor function, enhanced inhibition of tumour growth and increased survival. Cellular nanoporation may enable the use of exosomes as a universal nucleic-acid carrier for applications requiring transcriptional manipulation.
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In the citing paper
“Compared to exosomes produced endogenously without involving external stimuli, CNP-treated exosomes from cells of the same origin have an increased mRNA encapsulation efficiency of 3–4 folds.”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [110]
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In the citing paper
“A tumour suppressor gene, like phosphatase and tensin homologue (PTEN), is commonly mutated in wide ranges of GBM, which may be a great candidate for therapeutic intervention27,54.”
From Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system (2025) · cites this paper as [27]
Experimental — accuracy not yet measuredIn the citing paper
“The CNP technology increases the exosome yield and the mRNA amount within the exosomes [110].”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [110]
In the citing paper
“In addition, this strategy increased mRNA loading in exosomes by 100-fold compared to conventional electroporation methods.”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [110]
In the citing paper
“By modifying the exosome CD47 with these peptides, the targeting ability was improved.”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [110]
In the citing paper
“Chemical modification of exosomes was carried out to target GL261 gliomas and U87 glioblastomas.”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [110]
In the citing paper
“Moreover, when PTEN mRNA was additionally modified with the CDX peptide, the resulting exosomes exhibited a twofold increase in accumulation in mouse U87 gliomas, leading to prolonged survival.”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [110]
In the citing paper
“Similarly, modification of PTEN mRNA with CREKA peptide resulted in a 1.5-fold increase in accumulation in mouse U87 gliomas and improved survival [110].”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [110]
In the citing paper
“Yang et al. modified CD47-derived exosomes by incorporating a glioma targeting peptide at the N terminus. This modification allowed for selective uptake of tumor suppression gene, phosphatase and tensin homolog (PTEN) cargo by glioma cells. As a result, the proliferation of tumor cells was effectively inhibited [110].”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [110]
In the citing paper
“In Yang et al. research, mouse embryonic fibroblast-derived exosomes were able to deliver PTEN (phosphatase and homologous tensin) mRNA to inhibit mouse glioma growth [49].”
From The Therapeutic Potential and Clinical Significance of Exosomes as Carriers of Drug Delivery System (2022) · cites this paper as [49]
In the citing paper
“Naturally derived membrane lipids (for example, exosomes and cell membranes) can also be applied for mRNA delivery116,249,250.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [249]
In the citing paper
“However, large-scale production and purification of natural exosomes present significant challenges. Standardization of isolation techniques remains an area of ongoing research, with variations in yield and purity across different methods [36].”
From Emerging role of exosomes in cancer therapy: progress and challenges (2025) · cites this paper as [36]
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Citations
Cites
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Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth
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Self-citation
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Lipid nanoparticles for mRNA delivery
Hou, X., Zaks, T., Langer, R., & Dong, Y. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00358-0 · Cited by 4,076
Extracellular vesicles as a next-generation drug delivery platform
Herrmann, I. K., Wood, M. J. A., & Fuhrmann, G. (2021) · Nature Nanotechnology · doi:10.1038/s41565-021-00931-2 · Cited by 1,948
Lipids and Lipid Derivatives for RNA Delivery
Zhang, Y., Sun, C., Wang, C., Jankovic, K. E., & Dong, Y. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00244 · Cited by 649
Exosomes─Nature’s Lipid Nanoparticles, a Rising Star in Drug Delivery and Diagnostics
Tenchov, R., Sasso, J. M., Wang, X., Liaw, W., Chen, C., & Zhou, Q. A. (2022) · ACS Nano · doi:10.1021/acsnano.2c08774 · Cited by 642
Self-citationDesign of therapeutic biomaterials to control inflammation
Tu, Z., Zhong, Y., Hu, H., Shao, D., Haag, R., Schirner, M., Lee, J., Sullenger, B. A., & Leong, K. W. (2022) · Nature Reviews Materials · doi:10.1038/s41578-022-00426-z · Cited by 533
Metadata
- Authors
- Yang, Z., Shi, J., Xie, J., Wang, Y., Sun, J., Liu, T., Zhao, Y., Zhao, X., Wang, X., Ma, Y., Malkoc, V., Chiang, C., Deng, W., Chen, Y., Fu, Y., Kwak, K. J., Fan, Y., Kang, C., Yin, C., Rhee, J., Bertani, P., Otero, J., Lu, W., Yun, K., Lee, A. S., Jiang, W., Teng, L., Kim, B. Y. S., & Lee, L. J.
- Affiliations
- The Ohio State University (US)
- Jilin University (CN)
- The University of Texas Southwestern Medical Center (US)
- Jinan University (CN)
- Mayo Clinic (US)
- Peking University (CN)
- Institute for Stem Cell Biology and Regenerative Medicine (US)
- Houston Methodist Research Institute (US)
- Shenzhen Bay Laboratory (CN)
- Corresponding author
- Teng, Lesheng
- Kim, Betty Y. S.
- Lee, L. James
- ORCID
- Venue
- Nature Biomedical Engineering
- Published
- 2019-12-16
- Volume
- 4
- Issue
- 1
- Pages
- 69-83
- ISSN
- 2157-846X (ISSN-L)
- PMC
- PMC7080209
- OpenAlex
- W2995128645
- Cited by
- 744
- References
- 49
- Citations by year
- 2026: 81 · 2025: 125 · 2024: 135 · 2023: 128 · 2022: 117 · 2021: 101 · 2020: 56
- FWCI
- 22.67
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-06-15)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Biomedical Engineering (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (K08CA241070)
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (1R01NS104315)
- 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
- exosomes, mRNA delivery, electroporation, exosome production, targeting peptides, tumor suppression, nucleic acid carriers, exosome secretion, brain tumors
- MeSH terms
- Animals, Brain Neoplasms, Cells, Cultured, Disease Models, Animal, Glioma, Humans, Mice, Inbred C57BL, RNA, Messenger, Signal Transduction, Drug Delivery Systems, Electroporation, MicroRNAs, Nanotechnology, Exosomes, HEK293 Cells
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