{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T17:34:46Z","timestamp":1793468086359,"version":"4.5.0"},"reference-count":154,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging"],"abstract":"<jats:p>\n                    Rare neurological diseases (RND) represent a growing but underrecognized global health burden, particularly in aging populations in whom clinical manifestations appear later in life, resulting in substantial morbidity, reduced quality of life, and increased mortality. Advances in understanding and treating these diseases have been hindered by low prevalence, phenotypic heterogeneity, and complex molecular mechanisms. Importantly, shared genetic and mechanistic links between rare and common neurodegenerative disorders, such as\n                    <jats:italic>GBA1 (Glucosylceramidase Beta 1)<\/jats:italic>\n                    gene variant-associated Gaucher disease (GD) and Parkinson\u2019s disease (PD), highlight convergent biological pathways that may be leveraged for biomarker discovery and therapeutic innovation. Notably, individuals heterozygous for pathogenic\n                    <jats:italic>GBA1<\/jats:italic>\n                    variants, historically considered asymptomatic carriers, are now recognized to have an increased lifetime risk of developing PD and related synucleinopathies. This emerging evidence indicates that even single-allele variants can confer long-term neurological risk, reinforcing the continuum between rare monogenic disorders and more common neurodegenerative diseases. Extracellular Vesicles (EVs) have emerged as a promising, minimally invasive platform for advancing RND research, although translation remains limited by source specificity, vesicle heterogeneity, and incomplete clinical validation. By encapsulating proteins, lipids, and nucleic acids that reflect their cellular origin and disease state, EVs offer unique opportunities for early diagnosis, disease stratification, longitudinal monitoring, and assessment of treatment responses. In this review, we summarize fundamental aspects of EV biology and critically evaluate recent advances in EV-based biomarker discovery for RND, informed by translational insights from more prevalent neurodegenerative conditions. We further discuss the therapeutic potential of EVs, emphasizing their intrinsic biocompatibility, their reported capacity in selected preclinical settings to traverse biological barriers, including the blood-brain barrier, and their versatility as carriers for neuroprotective and gene-modifying cargo. Finally, we address key technical and translational challenges, including isolation, characterization, scalability, and regulatory considerations that currently limit clinical adoption. Collectively, this review highlights emerging opportunities and outlines an integrative translational perspective for EV-based diagnostic and therapeutic strategies into research and clinical paradigms for aging individuals affected by RND.\n                  <\/jats:p>","DOI":"10.3389\/fragi.2026.1813553","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:45:20Z","timestamp":1782279920000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Extracellular vesicles as minimally invasive biomarkers and therapeutic platforms in rare neurological diseases"],"prefix":"10.3389","volume":"7","author":[{"given":"Nathan D.","family":"Phan","sequence":"first","affiliation":[{"name":"Center for Orphan Drug Research, Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota","place":["Minneapolis, MN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghu Rai","family":"Sharma","sequence":"additional","affiliation":[{"name":"Center for Orphan Drug Research, Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota","place":["Minneapolis, MN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subbaya","family":"Subramanian","sequence":"additional","affiliation":[{"name":"Department of Surgery, Medical School, University of Minnesota","place":["Minneapolis, MN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reena V.","family":"Kartha","sequence":"additional","affiliation":[{"name":"Center for Orphan Drug Research, Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota","place":["Minneapolis, MN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"104647","DOI":"10.1016\/j.nbd.2019.104647","article-title":"A characterization of gaucher iPS-derived astrocytes: potential implications for Parkinson\u2019s disease","volume":"134","author":"Aflaki","year":"2020","journal-title":"Neurobiol. 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