Novel Endogenous Engineering Platform for Robust Loading and Delivery of Functional mRNA by Extracellular Vesicles
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.
Authors
- Omnia M. Elsharkasy
- Oscar P. B. Wiklander (ORCID: https://orcid.org/0000-0003-1176-8114)
- Mariacristina De Luca
- Xiuming Liang (ORCID: https://orcid.org/0000-0003-0202-1211)
- André Görgens (ORCID: https://orcid.org/0000-0001-9198-0857)
- Noriyasu Kamei (ORCID: https://orcid.org/0000-0002-5450-2562)
- Houze Zhou
- Doste R. Mamand
- Guannan Zhou (ORCID: https://orcid.org/0000-0001-9353-1908)
- Joel Z. Nordin (ORCID: https://orcid.org/0000-0002-3653-7710)
- Samantha Roudi (ORCID: https://orcid.org/0000-0003-3923-3410)
- Antje M. Zickler (ORCID: https://orcid.org/0000-0001-5001-6586)
- Virginia Castilla‐Llorente (ORCID: https://orcid.org/0000-0002-9081-7780)
- Lorenzo Errichelli (ORCID: https://orcid.org/0000-0002-1929-5078)
- Samir EL Andaloussi (ORCID: https://orcid.org/0000-0003-4468-9113)
- Giulia Corso (ORCID: https://orcid.org/0000-0002-1145-0862)
- Titash Sen (ORCID: https://orcid.org/0000-0001-5970-4879)
- Dhanu Gupta (ORCID: https://orcid.org/0000-0003-0163-2678)
- Justin Hean (ORCID: https://orcid.org/0000-0002-7291-080X)
- Zheyu Niu
Institutions
- Karolinska University Hospital (SE)
- Shandong University (CN)
- Kobe Gakuin University (JP)
- Karolinska Institutet (SE)
- University of Oxford (GB)
- Human Technopole (IT)
- Shandong Provincial Hospital (CN)
- Evercyte (Austria) (AT)
- Lonza (United Kingdom) (GB)
- Obstetrics and Gynecology Hospital of Fudan University (CN)
- Shandong First Medical University (CN)
- University of Duisburg-Essen (DE)
Publication Details
- Journal
- Advanced Science
- Published
- 2024-09-09
- DOI
- https://doi.org/10.1002/advs.202407619
- Citations
- 26
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 5.85
Funders
- European Commission
- Cancerfonden
- Karolinska Institutet
- Vetenskapsrådet
- Stiftelsen för Strategisk Forskning
- Horizon 2020 Framework Programme
- Center for Innovative Medicine
- HORIZON EUROPE European Research Council