{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T15:35:13Z","timestamp":1782315313582,"version":"3.54.5"},"reference-count":65,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,29]],"date-time":"2023-05-29T00:00:00Z","timestamp":1685318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1RO1 NS102412"],"award-info":[{"award-number":["1RO1 NS102412"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01NS112019-01A1"],"award-info":[{"award-number":["1R01NS112019-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["38-124"],"award-info":[{"award-number":["38-124"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Eshelman Institute for Innovation","award":["1RO1 NS102412"],"award-info":[{"award-number":["1RO1 NS102412"]}]},{"name":"Eshelman Institute for Innovation","award":["1R01NS112019-01A1"],"award-info":[{"award-number":["1R01NS112019-01A1"]}]},{"name":"Eshelman Institute for Innovation","award":["38-124"],"award-info":[{"award-number":["38-124"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Over the recent decades, the use of extracellular vesicles (EVs) has attracted considerable attention. Herein, we report the development of a novel EV-based drug delivery system for the transport of the lysosomal enzyme tripeptidyl peptidase-1 (TPP1) to treat Batten disease (BD). Endogenous loading of macrophage-derived EVs was achieved through transfection of parent cells with TPP1-encoding pDNA. More than 20% ID\/g was detected in the brain following a single intrathecal injection of EVs in a mouse model of BD, ceroid lipofuscinosis neuronal type 2 (CLN2) mice. Furthermore, the cumulative effect of EVs repetitive administrations in the brain was demonstrated. TPP1-loaded EVs (EV-TPP1) produced potent therapeutic effects, resulting in efficient elimination of lipofuscin aggregates in lysosomes, decreased inflammation, and improved neuronal survival in CLN2 mice. In terms of mechanism, EV-TPP1 treatments caused significant activation of the autophagy pathway, including altered expression of the autophagy-related proteins LC3 and P62, in the CLN2 mouse brain. We hypothesized that along with TPP1 delivery to the brain, EV-based formulations can enhance host cellular homeostasis, causing degradation of lipofuscin aggregates through the autophagy\u2013lysosomal pathway. Overall, continued research into new and effective therapies for BD is crucial for improving the lives of those affected by this condition.<\/jats:p>","DOI":"10.3390\/cells12111497","type":"journal-article","created":{"date-parts":[[2023,5,29]],"date-time":"2023-05-29T03:39:36Z","timestamp":1685331576000},"page":"1497","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Extracellular Vesicles Released by Genetically Modified Macrophages Activate Autophagy and Produce Potent Neuroprotection in Mouse Model of Lysosomal Storage Disorder, Batten Disease"],"prefix":"10.3390","volume":"12","author":[{"given":"Nazira","family":"El-Hage","sequence":"first","affiliation":[{"name":"Department of Immunology and Nanomedicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Haney","sequence":"additional","affiliation":[{"name":"Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"name":"Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuling","family":"Zhao","sequence":"additional","affiliation":[{"name":"Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"name":"Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3925-9023","authenticated-orcid":false,"given":"Myosotys","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Immunology and Nanomedicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanhong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Radiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mori","family":"Liu","sequence":"additional","affiliation":[{"name":"Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carson J.","family":"Swain","sequence":"additional","affiliation":[{"name":"Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0535-3214","authenticated-orcid":false,"given":"Hong","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Radiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9386-3790","authenticated-orcid":false,"given":"Elena V.","family":"Batrakova","sequence":"additional","affiliation":[{"name":"Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"name":"Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"867","DOI":"10.2174\/138920111795542633","article-title":"Therapeutic approaches to the challenge of neuronal ceroid lipofuscinoses","volume":"12","author":"Kohan","year":"2011","journal-title":"Curr. 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