Microvesicles (MVs) play an important role in intercellular communication by carrying mRNAs, microRNAs (miRNAs), non-coding RNAs, proteins, and DNA from cell to cell. To our knowledge, this is the first report of delivery of a therapeutic mRNA/protein via MVs for treatment of cancer. We first generated genetically engineered MVs by expressing high levels of the suicide gene mRNA and protein-cytosine deaminase (CD) fused to uracil phosphoribosyltransferase (UPRT) in MV donor cells. MVs were isolated from these cells and used to treat pre-established nerve sheath tumors (schwannomas) in an orthotopic mouse model. We demonstrated that MV-mediated delivery of CD-UPRT mRNA/protein by direct injection into schwannomas led to regression of these tumors upon systemic treatment with the prodrug (5-fluorocytosine (5-FC)), which is converted within tumor cells to 5-fluorouracil (5-FU)-an anticancer agent. Taken together, these studies suggest that MVs can serve as novel cell-derived "liposomes" to effectively deliver therapeutic mRNA/proteins to treatment of diseases.
Bibliographical noteFunding Information:
We thank Suzanne McDavitt for skilled editorial assistance and Shilpa Prabhakar for technical help. Support for this work was provided by NIH NCI grant CA141150 (X.O.B.), NIH NINDS grant NS037409 (X.O.B., O.S.), Forschungsgesellschaft for Brain Tumors (O.S.), EU-FP7-PEOPLE-2011-CIG (O.S.), and Association for conduct of scientific research in the field of neonatology and pediatric intensive care: “Unser Kind” (O.S.). The authors declared no conflict of interest.