# Neuron Specific mRNA Transfer With Fusogenic Microvesicles

> **NIH NIH R03** · UNIVERSITY OF COLORADO · 2022 · $78,250

## Abstract

Project Summary
Numerous studies have shown that RNAs can be transferred between specific types of
mammalian cells. Such exchanges are mostly limited to non-translatable RNA and mediated by
extracellular vesicles (EVs), which are known to be capable of encapsulating small RNAs
(microRNAs and small pieces mRNAs) and delivering them to the recipient cells. Recent studies
suggest that full-length mRNAs can be transferred intercellularly via by extracellular vesicles or
direct cell-cell contact. However, the mechanisms governing intercellular transfer of mRNAs and
the specificity of mRNAs transfer are still poorly understood. The efficiency of mRNA transfer is
also poor, which makes it difficult for therapeutic applications. We recently discovered that
expression of a single virus-derived protein called vesicular stomatitis virus G protein (VSV-G) in
mammalian cells can promote intercellular exchange of proteins and nucleic acids via highly
fusogenic microvesicles, which we call gectosomes (G protein ectosomes). We demonstrated
that VSV-G can stimulate: 1) outward budding of vesicles at the plasma membrane of donor cells;
2) internalization of vesicles into recipient cells; 3) efficient cargo release from endosomes inside
recipient cells; 4) gectosomes are hundreds fold more efficient in delivering bioactive proteins
than artificial liposomes. Due to the broad cellular tropism of VSV-G, gectosomes can mediate
intercellular transfer of proteins and RNAs rather nonspecifically between mammalian cells, which
would be a challenge for future development of cell or tissue specific delivery of mRNAs as a
therapeutic modality. Inspired by our findings with VSV-G, we searched for other VSV-G like
proteins for similar functions but with more restricted cellular tropism. We discovered a new viral
glycoprotein, CNV-G, from Chandipura vesiculovirus that shares many properties with VSV-G in
making gectosomes. Unlike VSV-G, CNV-G gectosomes show highly restricted cell tropism with
significant uptake only in neuronal cells. The central hypothesis of this proposal is that neuron-
specific glycoprotein CNV-G can be engineered to encapsulate functional mRNAs into
extracellular vesicles to be used to deliver potential therapeutic mRNAs to neuronal cells. The
objective of this application is to characterize the specificity of CNV-G gectosomes and
demonstrate that CNV-G gectosomes can mediate the transfer of cellular mRNAs to neuronal
cells and reprogram cellular protein contents. Methods for neuron-specific mRNA transfer will lay
the foundation to co-opt this system for developing mRNA such as BDNF as therapeutic drugs to
overcome the delivery challenges for delivering therapeutic mRNAs to neurons.

## Key facts

- **NIH application ID:** 10451377
- **Project number:** 1R03NS120072-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** XUEDONG LIU
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $78,250
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10451377

## Citation

> US National Institutes of Health, RePORTER application 10451377, Neuron Specific mRNA Transfer With Fusogenic Microvesicles (1R03NS120072-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10451377. Licensed CC0.

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