A platform for actively loading cargo RNA to elucidate limiting steps in EV‐mediated delivery
Open accessAbstract
Extracellular vesicles (EVs) mediate intercellular communication through transfer of RNA and protein between cells. Thus, understanding how cargo molecules are loaded and delivered by EVs is of central importance for elucidating the biological roles of EVs and developing EV‐based therapeutics. While some motifs modulating the loading of biomolecular cargo into EVs have been elucidated, the general rules governing cargo loading and delivery remain poorly understood. To investigate how general biophysical properties impact loading and delivery of RNA by EVs, we developed a platform for actively loading engineered cargo RNAs into EVs. In our system, the MS2 bacteriophage coat protein was fused to EV‐associated proteins, and the cognate MS2 stem loop was engineered into cargo RNAs. Using this Targeted and Modular EV Loading (TAMEL) approach, we identified a configuration that substantially enhanced cargo RNA loading (up to 6‐fold) into EVs. When applied to vesicles expressing the vesicular stomatitis virus glycoprotein (VSVG) – gesicles – we observed a 40‐fold enrichment in cargo RNA loading. While active loading of mRNA‐length (>1.5 kb) cargo molecules was possible, active loading was much more efficient for smaller (~0.5 kb) RNA molecules. We next leveraged the TAMEL platform to elucidate the limiting steps in EV‐mediated delivery of mRNA and protein to prostate cancer cells, as a model system. Overall, most cargo was rapidly degraded in recipient cells, despite high EV‐loading efficiencies and substantial EV uptake by recipient cells. While gesicles were efficiently internalized via a VSVG‐mediated mechanism, most cargo molecules were rapidly degraded. Thus, in this model system, inefficient endosomal fusion or escape likely represents a limiting barrier to EV‐mediated transfer. Altogether, the TAMEL platform enabled a comparative analysis elucidating a key opportunity for enhancing EV‐mediated delivery to prostate cancer cells, and this technology should be of general utility for investigations and applications of EV‐mediated transfer in other systems.
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The TAMEL system significantly increased RNA cargo loading up to sixfold.
“This approach significantly increased the RNA cargo loading up to sixfold.”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [99]
Applying TAMEL to exosomes expressing VSVG resulted in a 40-fold enrichment of cargo RNA load.
“Applying this method to exosomes expressing vesicular stomatitis virus glycoprotein (VSVG) resulted in a 40-fold enrichment of cargo RNA load (Fig. 3B) [99].”
From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [99]
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- Authors
- Hung, M. E., & Leonard, J. N.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Leonard, Joshua N.
- Venue
- Journal of Extracellular Vesicles
- Publisher
- Wiley
- Published
- 2016-01
- Volume
- 5
- Issue
- 1
- Pages
- 31027-31027
- ISSN
- 2001-3078 (ISSN-L)
- PMC
- PMC4870355
- OpenAlex
- W2357241585
- Cited by
- 251
- References
- 37
- Citations by year
- 2026: 27 · 2025: 29 · 2024: 37 · 2023: 36 · 2022: 32 · 2021: 23 · 2020: 24 · 2019: 12 · 2018: 12 · 2017: 16 · 2016: 3
- FWCI
- 7.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Extracellular Vesicles (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Arch
- Funders
- National Center for Research Resources (1S10RR025092)
- Chicago Community Trust
- National Institutes of Health (P50 CA090386)
- 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
- extracellular vesicles, vesicular stomatitis virus glycoprotein, endosomal escape, endosomal membrane fusion, prostate cancer cells, EV-based therapeutics
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