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Because HGSNAT is a trans\u2010lysosomal\u2010membrane protein, gene therapy for MPS IIIC needs to transduce as many cells as possible for maximal benefits. All cells continuously release extracellular vesicles (EVs) and communicate by exchanging biomolecules via EV trafficking. To address the unmet need, we developed a rAAV\u2010hHGSNAT<jats:sup>EV<\/jats:sup> vector with an EV\u2010mRNA\u2010packaging signal in the 3\u2032UTR to facilitate bystander effects, and tested it in an in vitro MPS IIIC model. In human MPS IIIC cells, rAAV\u2010hHGSNAT<jats:sup>EV<\/jats:sup> enhanced HGSNAT mRNA and protein expression, EV\u2010hHGSNAT\u2010mRNA packaging, and cleared GAG storage. Importantly, incubation with EVs led to hHGSNAT protein expression and GAG contents clearance in recipient MPS IIIC cells. Further, rAAV\u2010hHGSNAT<jats:sup>EV<\/jats:sup> transduction led to the reduction of pathological EVs in MPS IIIC cells to normal levels, suggesting broader therapeutic benefits. These data demonstrate that incorporating the EV\u2010mRNA\u2010packaging signal into a rAAV\u2010hHGSNAT vector enhances EV packaging of hHGSNAT\u2010mRNA, which can be transported to non\u2010transduced cells and translated into functional rHGSNAT protein, facilitating cross\u2010correction of disease pathology. This study supports the therapeutic potential of rAAV<jats:sup>EV<\/jats:sup> for MPS IIIC, and broad diseases, without having to transduce every cell.<\/jats:p>","DOI":"10.1002\/jev2.12464","type":"journal-article","created":{"date-parts":[[2024,7,4]],"date-time":"2024-07-04T00:26:05Z","timestamp":1720052765000},"source":"Crossref","is-referenced-by-count":6,"title":["AAV gene replacement therapy for treating MPS IIIC: Facilitating bystander effects via EV\u2010mRNA cargo"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1624-5067","authenticated-orcid":false,"given":"Tierra A.","family":"Bobo","sequence":"first","affiliation":[{"name":"Gene Therapy Center  Chapel Hill USA"},{"name":"Division of Genetics and Metabolism, Department of Pediatrics School of Medicine  Chapel Hill USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Robinson","sequence":"additional","affiliation":[{"name":"Gene Therapy Center  Chapel 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