Intradermally delivered mRNA-encapsulating extracellular vesicles for collagen-replacement therapy
Abstract
The success of messenger RNA therapeutics largely depends on the availability of delivery systems that enable the safe, effective and stable translation of genetic material into functional proteins. Here we show that extracellular vesicles (EVs) produced via cellular nanoporation from human dermal fibroblasts, and encapsulating mRNA encoding for extracellular-matrix α1 type-I collagen (COL1A1) induced the formation of collagen-protein grafts and reduced wrinkle formation in the collagen-depleted dermal tissue of mice with photoaged skin. We also show that the intradermal delivery of the mRNA-loaded EVs via a microneedle array led to the prolonged and more uniform synthesis and replacement of collagen in the dermis of the animals. The intradermal delivery of EV-based COL1A1 mRNA may make for an effective protein-replacement therapy for the treatment of photoaged skin.
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Intradermal delivery of exosome loaded with mRNA using a microneedle array improved and prolonged collagen synthesis and replacement in animal dermis.
“In addition, intradermal delivery of exosome loaded with mRNA using a microneedle array improved and prolonged collagen synthesis and replacement in the animal dermis [111].”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [111]
These exosomes promoted collagen grafts formation and reduced formation of wrinkles in photoaging dermal collagen depletion mice model.
“These exosomes promoted the collagen grafts formation and reduced the formation of wrinkles in the photoaging dermal collagen depletion mice model.”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [111]
Exosomes generated from human dermal fibroblasts via CNP are loaded with mRNA encoding COL1A1.
“Exosomes generated from human dermal fibroblasts via CNP are loaded with mRNA encoding ECM α1 type I collagen (COL1A1).”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [111]
Cites
Valadi, H., Ekström, K., Bossios, A., Sjöstrand, M., Lee, J. J., & Lötvall, J. O. (2007) · Nature Cell Biology · doi:10.1038/ncb1596 · Cited by 12,834 · see citing works
Shedding light on the cell biology of extracellular vesicles
van Niel, G., D'Angelo, G., & Raposo, G. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.125 · Cited by 8,369 · see citing works
Poly(ethylene glycol) in Drug Delivery: Pros and Cons as Well as Potential Alternatives
Knop, K., Hoogenboom, R., Fischer, D., & Schubert, U. S. (2010) · Angewandte Chemie International Edition · doi:10.1002/anie.200902672 · Cited by 3,533 · see citing works
Non-viral vectors for gene-based therapy
Yin, H., Kanasty, R. L., Eltoukhy, A. A., Vegas, A. J., Dorkin, J. R., & Anderson, D. G. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3763 · Cited by 3,123 · see citing works
Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer
Kamerkar, S., LeBleu, V. S., Sugimoto, H., Yang, S., Ruivo, C. F., Melo, S. A., Lee, J. J., & Kalluri, R. (2017) · Nature · doi:10.1038/nature22341 · Cited by 2,639 · see citing works
mRNA-based therapeutics--developing a new class of drugs
Sahin, U., Karikó, K., & Türeci, Ö. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4278 · Cited by 2,474 · see citing works
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 1,951 · see citing works
RNA delivery by extracellular vesicles in mammalian cells and its applications
O’Brien, K., Breyne, K., Ughetto, S., Laurent, L. C., & Breakefield, X. O. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0251-y · Cited by 1,811 · see citing works
mRNA vaccines for infectious diseases: principles, delivery and clinical translation
Chaudhary, N., Weissman, D., & Whitehead, K. A. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00283-5 · Cited by 1,555 · see citing works
Pathophysiology of Premature Skin Aging Induced by Ultraviolet Light
Fisher, G. J., Wang, Z., Datta, S. C., Varani, J., Kang, S., & Voorhees, J. J. (1997) · New England Journal of Medicine · doi:10.1056/nejm199711133372003 · Cited by 1,501 · see citing works
Drug delivery systems for RNA therapeutics
Paunovska, K., Loughrey, D., & Dahlman, J. E. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-021-00439-4 · Cited by 1,349 · see citing works
Extracellular vesicles for drug delivery.
Vader, P., Mol, E. A., Pasterkamp, G., & Schiffelers, R. M. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2016.02.006 · Cited by 1,237 · see citing works
Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery
Kowalski, P. S., Rudra, A., Miao, L., & Anderson, D. G. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.02.012 · Cited by 1,127 · see citing works
Tanaka, M., Yamamoto, Y., Misawa, E., Nabeshima, K., Saito, M., Yamauchi, K., Abe, F., & Furukawa, F. (2016) · Skin Pharmacology and Physiology · doi:10.1159/000454718 · Cited by 1,092 · see citing works
Decreased Collagen Production in Chronologically Aged Skin
Varani, J., Dame, M. K., Rittie, L., Fligiel, S. E. G., Kang, S., Fisher, G. J., & Voorhees, J. J. (2006) · The American Journal of Pathology · doi:10.2353/ajpath.2006.051302 · Cited by 910 · see citing works
Yu, J., Zhang, Y., Ye, Y., DiSanto, R., Sun, W., Ranson, D., Ligler, F. S., Buse, J. B., & Gu, Z. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1505405112 · Cited by 852 · see citing works
Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation
Yang, Z., Shi, J., Xie, J., Wang, Y., Sun, J., Liu, T., Zhao, Y., Zhao, X., Wang, X., Ma, Y., et al. (2019) · Nature Biomedical Engineering · doi:10.1038/s41551-019-0485-1 · Cited by 744 · see citing works
Self-citationTherapeutically harnessing extracellular vesicles
Cheng, L., & Hill, A. F. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00410-w · Cited by 737 · see citing works
Looking Older: Fibroblast Collapse and Therapeutic Implications
Fisher, G. J., Varani, J., & Voorhees, J. J. (2008) · Archives of Dermatology · doi:10.1001/archderm.144.5.666 · Cited by 540 · see citing works
Shi, D., Beasock, D., Fessler, A., Szebeni, J., Ljubimova, J. Y., Afonin, K. A., & Dobrovolskaia, M. A. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.114079 · Cited by 535 · see citing works
Pi, F., Binzel, D. W., Lee, T. J., Li, Z., Sun, M., Rychahou, P. G., Li, H., Haque, F., Wang, S., Croce, C. M., et al. (2017) · Nature Nanotechnology · doi:10.1038/s41565-017-0012-z · Cited by 495 · see citing works
Self-citationSkin models for the testing of transdermal drugs
Abd, E., Yousuf, S. A., Pastore, M. N., Telaprolu, K. C., Mohammed, Y., Namjoshi, S., Grice, J. E., & Roberts, M. S. (2016) · Clinical Pharmacology Advances and Applications · doi:10.2147/cpaa.s64788 · Cited by 418 · see citing works
Kim, S., Lechman, E. R., Bianco, N. R., Menon, R., Keravala, A., Nash, J. A., Mi, Z., Watkins, S. C., Gambotto, A. A., & Robbins, P. D. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.10.6440 · Cited by 380 · see citing works
Neutralization of SARS-CoV-2 Omicron by BNT162b2 mRNA vaccine–elicited human sera
Muik, A., Lui, B. G., Wallisch, A.-K., Bacher, M., Mühl, J., Reinholz, J., Ozhelvaci, O., Beckmann, N., Güimil Garcia, R. D. L. C., Poran, A., et al. (2022) · Science · doi:10.1126/science.abn7591 · Cited by 367 · see citing works
Extracellular matrix regulation of fibroblast function: redefining our perspective on skin aging
Cole, M. A., Quan, T., Voorhees, J. J., & Fisher, G. J. (2018) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-018-0459-1 · Cited by 365 · see citing works
Drug Delivery with Extracellular Vesicles: From Imagination to Innovation
de Jong, O. G., Kooijmans, S. A. A., Murphy, D. E., Jiang, L., Evers, M. J. W., Sluijter, J. P. G., Vader, P., & Schiffelers, R. M. (2019) · Accounts of Chemical Research · doi:10.1021/acs.accounts.9b00109 · Cited by 358 · see citing works
Droplet-born air blowing: Novel dissolving microneedle fabrication
Kim, J. D., Kim, M., Yang, H., et al. (2013) · Journal of Controlled Release · doi:10.1016/j.jconrel.2013.05.026 · Cited by 326 · see citing works
Hu, S., Li, Z., Cores, J., Huang, K., Su, T., Dinh, P., & Cheng, K. (2019) · ACS Nano · doi:10.1021/acsnano.9b04384 · Cited by 292 · see citing works
Self-citationThe delivery challenge: fulfilling the promise of therapeutic genome editing
van Haasteren, J., Li, J., Scheideler, O. J., Murthy, N., & Schaffer, D. V. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0565-5 · Cited by 285 · see citing works
Mycosporine-Like Amino Acids and Their Derivatives as Natural Antioxidants
Wada, N., Sakamoto, T., & Matsugo, S. (2015) · Antioxidants · doi:10.3390/antiox4030603 · Cited by 283 · see citing works
Lipid Nanoparticle–mRNA Formulations for Therapeutic Applications
Wang, C., Zhang, Y., & Dong, Y. (2021) · Accounts of Chemical Research · doi:10.1021/acs.accounts.1c00550 · Cited by 270 · see citing works
A Review on Electroporation-Based Intracellular Delivery
Shi, J., Ma, Y., Zhu, J., Chen, Y., Sun, Y., Yao, Y., Yang, Z., & Xie, J. (2018) · Molecules · doi:10.3390/molecules23113044 · Cited by 267 · see citing works
Self-citationQuan, T., Wang, F., Shao, Y., Rittié, L., Xia, W., Orringer, J. S., Voorhees, J. J., & Fisher, G. J. (2012) · Journal of Investigative Dermatology · doi:10.1038/jid.2012.364 · Cited by 248 · see citing works
Szebeni, J., Storm, G., Ljubimova, J. Y., Castells, M., Phillips, E. J., Turjeman, K., Barenholz, Y., Crommelin, D. J. A., & Dobrovolskaia, M. A. (2022) · Nature Nanotechnology · doi:10.1038/s41565-022-01071-x · Cited by 169 · see citing works
Developing Biodegradable Lipid Nanoparticles for Intracellular mRNA Delivery and Genome Editing
Qiu, M., Li, Y., Bloomer, H., & Xu, Q. (2021) · Accounts of Chemical Research · doi:10.1021/acs.accounts.1c00500 · Cited by 168 · see citing works
Wu, T. S., Hou, X. L., Li, J., et al. (2021) · ACS Nano · doi:10.1021/acsnano.1c07829 · Cited by 151 · see citing works
Allergic reactions and anaphylaxis to LNP-based COVID-19 vaccines
Moghimi, S. M. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.01.030 · Cited by 150 · see citing works
Fibroblast Growth Factors: A Controlling Mechanism of Skin Aging
de Araújo, R., Lôbo, M., Trindade, K., Silva, D. F., & Pereira, N. D. P. (2019) · Skin Pharmacology and Physiology · doi:10.1159/000501145 · Cited by 146 · see citing works
Mild Innate Immune Activation Overrides Efficient Nanoparticle‐Mediated RNA Delivery
Lokugamage, M. P., Gan, Z., Zurla, C., Levin, J., Islam, F. Z., Kalathoor, S., Sato, M., Sago, C. D., Santangelo, P. J., & Dahlman, J. E. (2020) · Advanced Materials · doi:10.1002/adma.201904905 · Cited by 126 · see citing works
Immunosuppressive Effects of Mesenchymal Stem Cells-derived Exosomes
Qian, X., An, N., Ren, Y., Yang, C., Zhang, X., & Li, L. (2020) · Stem Cell Reviews and Reports · doi:10.1007/s12015-020-10040-7 · Cited by 123 · see citing works
Choi, J. S., Cho, W. L., Choi, Y. J., Kim, J. D., Park, H., Kim, S. Y., Park, J. H., Jo, D., & Cho, Y. W. (2019) · Journal of Extracellular Vesicles · doi:10.1080/20013078.2019.1565885 · Cited by 122 · see citing works
Buranasudja, V., Rani, D., Malla, A., Kobtrakul, K., & Vimolmangkang, S. (2021) · Scientific Reports · doi:10.1038/s41598-021-92958-7 · Cited by 112 · see citing works
Gene therapy community grapples with toxicity issues, as pipeline matures
Mullard, A. (2021) · Nature Reviews Drug Discovery · doi:10.1038/d41573-021-00164-x · Cited by 112 · see citing works
Exosome-based <i>Ldlr</i> gene therapy for familial hypercholesterolemia in a mouse model
Li, Z., Zhao, P., Zhang, Y., Wang, J., Wang, C., Liu, Y., Yang, G., & Yuan, L. (2021) · Theranostics · doi:10.7150/thno.49874 · Cited by 108 · see citing works
Self-citationCao, H., Yue, Z. D., Gao, H., Chen, C., Cui, K., Zhang, K., Cheng, Y., Shao, G., Kong, D., Li, Z., et al. (2019) · ACS Nano · doi:10.1021/acsnano.8b09776 · Cited by 93 · see citing works
Self-citationSkin Pigmentation Abnormalities and Their Possible Relationship with Skin Aging
Lee, A.-Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073727 · Cited by 87 · see citing works
Self-citationZheng, T.-T., Pu, J.-L., Chen, Y.-X., Mao, Y.-F., Guo, Z., Pan, H.-Y., Zhang, L., Zhang, H., Sun, B.-G., & Zhang, B. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00012 · Cited by 81 · see citing works
Self-citationSong, H., Zhang, S., Zhang, L., & Li, B. (2017) · Nutrients · doi:10.3390/nu9111209 · Cited by 68 · see citing works
Anti-Wrinkle Benefits of Peptides Complex Stimulating Skin Basement Membrane Proteins Expression
Jeong, S., Yoon, S., Kim, S., Jung, J., Kor, M., Shin, K., Lim, C., Han, H. S., Lee, H., Park, K.-Y., et al. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms21010073 · Cited by 64 · see citing works
Novel approaches for managing aged skin and nonmelanoma skin cancer
Todorova, K. A., & Mandinova, A. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.06.004 · Cited by 59 · see citing works
Sharma, M. R., Werth, B. B., & Werth, V. P. (2011) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.2011.00911.x · Cited by 56 · see citing works
Concomitant Use of Hyaluronic Acid and Laser in Facial Rejuvenation
Urdiales‐Gálvez, F., Martín-Sánchez, S., Maíz-Jiménez, M., et al. (2019) · Aesthetic Plastic Surgery · doi:10.1007/s00266-019-01393-7 · Cited by 56 · see citing works
COL1A1: A potential therapeutic target for colorectal cancer expressing wild-type or mutant KRAS
Zhang, Z., Fang, C., Wang, Y., Zhang, J., Yu, J., Zhang, Y., Wang, X., & Zhong, J. (2018) · International Journal of Oncology · doi:10.3892/ijo.2018.4536 · Cited by 53 · see citing works
Self-citationKim, J. H., Kwon, T.-R., Lee, S. E., Jang, Y. N., Han, H. S., Mun, S. K., & Kim, B. J. (2020) · Scientific Reports · doi:10.1038/s41598-020-61952-w · Cited by 53 · see citing works
Self-citationTherapeutic potential of extracellular vesicle‐associated long noncoding RNA
Born, L. J., Harmon, J. W., & Jay, S. M. (2020) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10172 · Cited by 53 · see citing works
In vivo study of the effects of a portable cold plasma device and vitamin C for skin rejuvenation
Shakouri, R., Khani, M. R., Samsavar, S., Jezeh, M. A., Abdollahimajd, F., Hosseini, S. I., Dilmaghanian, A., Ghasemi, E., Alihoseini, M., & Shokri, B. (2021) · Scientific Reports · doi:10.1038/s41598-021-01341-z · Cited by 30 · see citing works
Cellular retinoic acid binding protein-II expression and its potential role in skin aging
Bielli, A., Scioli, M. G., D’Amico, F., Tarquini, C., Agostinelli, S., Costanza, G., Doldo, E., Campione, E., Passeri, D., Coniglione, F., et al. (2019) · Aging · doi:10.18632/aging.101813 · Cited by 19 · see citing works
Effect of repeated ultraviolet irradiation on skin of hairless mice
Alpermann, H. G., & Vogel, H. (1978) · Archives of Dermatological Research · doi:10.1007/bf00455569 · Cited by 18 · see citing works
Functional therapies for cutaneous wound repair in epidermolysis bullosa
Peking, P., Koller, U., & Murauer, E. M. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.12.003 · Cited by 16 · see citing works
Ultraviolet radiation protection potentials of Methylene Blue for human skin and coral reef health
Xiong, Z., Mao, X., Trappio, M., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-89970-2 · Cited by 13 · see citing works
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Exosome for mRNA delivery: Strategies and therapeutic applications
Iqbal, Z., Rehman, K., Mahmood, A., Shabbir, M., Liang, Y., Duan, L., & Zeng, H. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02634-x · Cited by 144 · see citing works
- Authors
- You, Y., Tian, Y., Yang, Z., Shi, J., Kwak, K. J., Tong, Y., Estania, A. P., Cao, J., Hsu, W.-H., Liu, Y., Chiang, C.-L., Schrank, B. R., Huntoon, K., Lee, D., Li, Z., Zhao, Y., Zhang, H., Gallup, T. D., Ha, J., Dong, S., Li, X., Wang, Y., Lu, W.-J., Bahrani, E., Lee, L. J., Teng, L., Jiang, W., Lan, F., Kim, B. Y. S., & Lee, A. S.
- Affiliations
- Peking University (CN)
- The University of Texas MD Anderson Cancer Center (US)
- The Ohio State University (US)
- Jilin University (CN)
- Vanderbilt University Medical Center (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Lan, Feng
- Kim, Betty Y. S.
- Lee, Andrew S.
- ORCID
- You, Yi
- Tian, Yu
- Yang, Zhaogang
- Tong, Yuhao
- Cao, Jianhong
- Hsu, Wei-Hsiang
- Liu, Yutong
- Chiang, Chi-Ling
- Schrank, Benjamin R.
- Huntoon, Kristin
- Lee, DaeYong
- Li, Ziwei
- Zhao, Yarong
- Zhang, Huan
- Gallup, Thomas D.
- Dong, Shiyan
- Li, Xuefeng
- Wang, Yifan
- Bahrani, Eman
- Lee, Ly James
- Teng, Lesheng
- Jiang, Wen
- Lan, Feng
- Kim, Betty Y. S.
- Lee, Andrew S.
- Venue
- Nature Biomedical Engineering
- Published
- 2023-01-12
- Volume
- 7
- Issue
- 7
- Pages
- 887-900
- ISSN
- 2157-846X (ISSN-L)
- OpenAlex
- W4315707390
- Cited by
- 258
- References
- 60
- Citations by year
- 2026: 56 · 2025: 93 · 2024: 83 · 2023: 26
- FWCI
- 22.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Biomedical Engineering (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Texas MD Anderson Cancer Center
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- extracellular vesicles, mRNA delivery, intradermal drug delivery, microneedle arrays, COL1A1, photodamaged skin, dermal fibroblasts, skin collagen, wrinkle formation, protein replacement therapy
- MeSH terms
- Extracellular Vesicles, Animals, Collagen, Humans, RNA, Messenger, Skin, Dermis, Mice
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