Novel Endogenous Engineering Platform for Robust Loading and Delivery of Functional mRNA by Extracellular Vesicles
Abstract Messenger RNA (mRNA) has emerged as an attractive therapeutic molecule for a plethora of clinical applications. For in vivo functionality, mRNA therapeutics require encapsulation into effective, stable, and safe delivery systems to protect the cargo from degradation and reduce immunogenicit...
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| Format: | Article |
| Language: | English |
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Wiley
2024-11-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202407619 |
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| author | Antje M. Zickler Xiuming Liang Dhanu Gupta Doste R. Mamand Mariacristina De Luca Giulia Corso Lorenzo Errichelli Justin Hean Titash Sen Omnia M. Elsharkasy Noriyasu Kamei Zheyu Niu Guannan Zhou Houze Zhou Samantha Roudi Oscar P. B. Wiklander André Görgens Joel Z. Nordin Virginia Castilla‐Llorente Samir EL Andaloussi |
| author_facet | Antje M. Zickler Xiuming Liang Dhanu Gupta Doste R. Mamand Mariacristina De Luca Giulia Corso Lorenzo Errichelli Justin Hean Titash Sen Omnia M. Elsharkasy Noriyasu Kamei Zheyu Niu Guannan Zhou Houze Zhou Samantha Roudi Oscar P. B. Wiklander André Görgens Joel Z. Nordin Virginia Castilla‐Llorente Samir EL Andaloussi |
| author_sort | Antje M. Zickler |
| collection | DOAJ |
| description | Abstract Messenger RNA (mRNA) has emerged as an attractive therapeutic molecule for a plethora of clinical applications. For in vivo functionality, mRNA therapeutics require encapsulation into effective, stable, and safe delivery systems to protect the cargo from degradation and reduce immunogenicity. Here, a bioengineering platform for efficient mRNA loading and functional delivery using bionormal nanoparticles, extracellular vesicles (EVs), is established by expressing a highly specific RNA‐binding domain fused to CD63 in EV producer cells stably expressing the target mRNA. The additional combination with a fusogenic endosomal escape moiety, Vesicular Stomatitis Virus Glycoprotein, enables functional mRNA delivery in vivo at doses substantially lower than currently used clinically with synthetic lipid‐based nanoparticles. Importantly, the application of EVs loaded with effective cancer immunotherapy proves highly effective in an aggressive melanoma mouse model. This technology addresses substantial drawbacks currently associated with EV‐based nucleic acid delivery systems and is a leap forward to clinical EV applications. |
| format | Article |
| id | doaj-art-57285ee9b4914259979d9194d408bdbc |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-57285ee9b4914259979d9194d408bdbc2025-08-20T01:51:14ZengWileyAdvanced Science2198-38442024-11-011142n/an/a10.1002/advs.202407619Novel Endogenous Engineering Platform for Robust Loading and Delivery of Functional mRNA by Extracellular VesiclesAntje M. Zickler0Xiuming Liang1Dhanu Gupta2Doste R. Mamand3Mariacristina De Luca4Giulia Corso5Lorenzo Errichelli6Justin Hean7Titash Sen8Omnia M. Elsharkasy9Noriyasu Kamei10Zheyu Niu11Guannan Zhou12Houze Zhou13Samantha Roudi14Oscar P. B. Wiklander15André Görgens16Joel Z. Nordin17Virginia Castilla‐Llorente18Samir EL Andaloussi19Division of Biomolecular and Cellular Medicine Department of Laboratory Medicine Karolinska Institutet ANA Futura Alfred‐Nobels‐Allé 8, Huddinge Stockholm 14152 SwedenDivision of Biomolecular and Cellular Medicine Department of Laboratory Medicine Karolinska Institutet ANA Futura Alfred‐Nobels‐Allé 8, Huddinge Stockholm 14152 SwedenDivision of Biomolecular and Cellular Medicine Department of Laboratory Medicine Karolinska Institutet ANA Futura Alfred‐Nobels‐Allé 8, Huddinge Stockholm 14152 SwedenDivision of Biomolecular and Cellular Medicine Department of Laboratory Medicine Karolinska Institutet ANA Futura Alfred‐Nobels‐Allé 8, Huddinge Stockholm 14152 SwedenEvox Therapeutics Ltd. Oxford Science Park Medawar Centre Robert Robinson Avenue Oxford OX4 4HG UKDivision of Biomolecular and Cellular Medicine Department of Laboratory Medicine Karolinska Institutet ANA Futura Alfred‐Nobels‐Allé 8, Huddinge Stockholm 14152 SwedenEvox Therapeutics Ltd. Oxford Science Park Medawar Centre Robert Robinson Avenue Oxford OX4 4HG UKEvox Therapeutics Ltd. Oxford Science Park Medawar Centre Robert Robinson Avenue Oxford OX4 4HG UKEvox Therapeutics Ltd. Oxford Science Park Medawar Centre Robert Robinson Avenue Oxford OX4 4HG UKDivision of Biomolecular and Cellular Medicine Department of Laboratory Medicine Karolinska Institutet ANA Futura Alfred‐Nobels‐Allé 8, Huddinge Stockholm 14152 SwedenDivision of Biomolecular and Cellular Medicine Department of Laboratory Medicine Karolinska Institutet ANA Futura Alfred‐Nobels‐Allé 8, Huddinge Stockholm 14152 SwedenDivision of Biomolecular and Cellular Medicine Department of Laboratory Medicine Karolinska Institutet ANA Futura Alfred‐Nobels‐Allé 8, Huddinge Stockholm 14152 SwedenDivision of Biomolecular and Cellular Medicine Department of Laboratory Medicine Karolinska Institutet ANA Futura Alfred‐Nobels‐Allé 8, Huddinge Stockholm 14152 SwedenDivision of Biomolecular and Cellular Medicine Department of Laboratory Medicine Karolinska Institutet ANA Futura Alfred‐Nobels‐Allé 8, Huddinge Stockholm 14152 SwedenDivision of Biomolecular and Cellular Medicine Department of Laboratory Medicine Karolinska Institutet ANA Futura Alfred‐Nobels‐Allé 8, Huddinge Stockholm 14152 SwedenDivision of Biomolecular and Cellular Medicine Department of Laboratory Medicine Karolinska Institutet ANA Futura Alfred‐Nobels‐Allé 8, Huddinge Stockholm 14152 SwedenDivision of Biomolecular and Cellular Medicine Department of Laboratory Medicine Karolinska Institutet ANA Futura Alfred‐Nobels‐Allé 8, Huddinge Stockholm 14152 SwedenDivision of Biomolecular and Cellular Medicine Department of Laboratory Medicine Karolinska Institutet ANA Futura Alfred‐Nobels‐Allé 8, Huddinge Stockholm 14152 SwedenEvox Therapeutics Ltd. Oxford Science Park Medawar Centre Robert Robinson Avenue Oxford OX4 4HG UKDivision of Biomolecular and Cellular Medicine Department of Laboratory Medicine Karolinska Institutet ANA Futura Alfred‐Nobels‐Allé 8, Huddinge Stockholm 14152 SwedenAbstract Messenger RNA (mRNA) has emerged as an attractive therapeutic molecule for a plethora of clinical applications. For in vivo functionality, mRNA therapeutics require encapsulation into effective, stable, and safe delivery systems to protect the cargo from degradation and reduce immunogenicity. Here, a bioengineering platform for efficient mRNA loading and functional delivery using bionormal nanoparticles, extracellular vesicles (EVs), is established by expressing a highly specific RNA‐binding domain fused to CD63 in EV producer cells stably expressing the target mRNA. The additional combination with a fusogenic endosomal escape moiety, Vesicular Stomatitis Virus Glycoprotein, enables functional mRNA delivery in vivo at doses substantially lower than currently used clinically with synthetic lipid‐based nanoparticles. Importantly, the application of EVs loaded with effective cancer immunotherapy proves highly effective in an aggressive melanoma mouse model. This technology addresses substantial drawbacks currently associated with EV‐based nucleic acid delivery systems and is a leap forward to clinical EV applications.https://doi.org/10.1002/advs.202407619bioengineeringcancer immunotherapydrug deliveryextracellular vesiclesnanotechnologynucleic acid therapeutics |
| spellingShingle | Antje M. Zickler Xiuming Liang Dhanu Gupta Doste R. Mamand Mariacristina De Luca Giulia Corso Lorenzo Errichelli Justin Hean Titash Sen Omnia M. Elsharkasy Noriyasu Kamei Zheyu Niu Guannan Zhou Houze Zhou Samantha Roudi Oscar P. B. Wiklander André Görgens Joel Z. Nordin Virginia Castilla‐Llorente Samir EL Andaloussi Novel Endogenous Engineering Platform for Robust Loading and Delivery of Functional mRNA by Extracellular Vesicles Advanced Science bioengineering cancer immunotherapy drug delivery extracellular vesicles nanotechnology nucleic acid therapeutics |
| title | Novel Endogenous Engineering Platform for Robust Loading and Delivery of Functional mRNA by Extracellular Vesicles |
| title_full | Novel Endogenous Engineering Platform for Robust Loading and Delivery of Functional mRNA by Extracellular Vesicles |
| title_fullStr | Novel Endogenous Engineering Platform for Robust Loading and Delivery of Functional mRNA by Extracellular Vesicles |
| title_full_unstemmed | Novel Endogenous Engineering Platform for Robust Loading and Delivery of Functional mRNA by Extracellular Vesicles |
| title_short | Novel Endogenous Engineering Platform for Robust Loading and Delivery of Functional mRNA by Extracellular Vesicles |
| title_sort | novel endogenous engineering platform for robust loading and delivery of functional mrna by extracellular vesicles |
| topic | bioengineering cancer immunotherapy drug delivery extracellular vesicles nanotechnology nucleic acid therapeutics |
| url | https://doi.org/10.1002/advs.202407619 |
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