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Because transcriptional and metabolic disturbances, notably mitochondrial dysfunction and oxidative stress, often occur before protein aggregation and synaptic loss, exRNAs enable minimally invasive access to early disease biology. Mechanistic evidence shows selective RNA packaging and delivery where transferred mRNAs can be translated and miRNAs can regulate targets. Clinical and preclinical data support a dual role as biomarkers and active mediators of pathology. Key barriers to reproducibility include pre-analytical variability, isolation heterogeneity, and uncertain cellular origin; recommended solutions involve standardized workflows, carrier- and cell type-specific enrichment, multimodal integration with proteomics/metabolomics and neuroimaging, and large longitudinal validation to enable robust clinical assays and interventions in neurodegeneration.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/extracellular-rnas-as-messengers-and-early-biomarkers-in-neurodegeneration-review/461810/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/extracellular-rnas-as-messengers-and-early-biomarkers-in-neurodegeneration-review/461810.png","ImageObject",300,407,{"name":92,"@type":93},"Patrick","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-08","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":19},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What makes extracellular RNAs suitable for early neurodegeneration biomarkers?","Question",{"text":112,"@type":113},"ExRNAs are detectable in biofluids and remain stable through protection by carriers such as extracellular vesicles, RNA-binding proteins, and lipoproteins. Early transcriptional and metabolic disturbances—including mitochondrial dysfunction and oxidative stress—often precede overt pathology, enabling early detection.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do exRNAs act beyond biomarker reporting?",{"text":117,"@type":113},"Mechanistic studies show selective packaging and delivery: transferred mRNAs can be translated, and EV-shuttled miRNAs can repress target mRNAs. This supports the idea that exRNAs can actively influence recipient cell gene-expression networks.",{"name":119,"@type":110,"acceptedAnswer":120},"Why is reproducibility difficult in exRNA studies?",{"text":121,"@type":113},"Major limitations include pre-analytical variability, isolation heterogeneity, and uncertain cellular origin of exRNAs. These factors can hinder consistent detection and comparison across studies.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},461810,1791390719,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":19,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},549758146520,"https://ap-avatar.wpscdn.com/avatar/80002397d8c0411e94?_k=1775819394049821470","Review  \nExtracellular RNAs as Messengers and Early Biomarkers in Neurodegeneration  \nKaidong Lu 1,2,3 and Magdalena J. Koziol 2,3, *  \nAcademic Editor: Maria Anttonietta Panaro  \nReceived: 27 November 2025  \nRevised: 16 December 2025  \nAccepted: 24 December 2025  \nPublished: 27 December 2025  \nCopyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \n1 College of Biological Sciences, China Agricultural University, Beijing 100193, China  \n2 Beijing Institute for Brain Research, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 102206, China  \n3 Chinese Institute for Brain Research, Beijing, Beijing 102206, China  \n* [Correspondence: mjk@cibr.ac.cn](Correspondence: mjk@cibr.ac.cn)  \nAbstract  \nExtracellular RNAs are released from cells and circulate stably in biofluids such as blood, cerebrospinal fluid, saliva, and urine via carriers including extracellular vesicles, RNAbinding proteins and lipoproteins. Because transcriptional and metabolic disturbances—notably mitochondrial dysfunction and oxidative stress—often precede protein aggregation, synaptic loss, and structural change in many brain diseases, exRNAs offer minimally invasive access to early disease biology. Mechanistic studies demonstrate selective RNA packaging and delivery: transferred mRNAs can be translated and miRNAs can modulate targets, indicating exRNAs both report intracellular programs and actively influence recipient cells. Clinical and preclinical data support a dual role for exRNAs as biomarkers and as mediators of pathology. Key technical hurdles—pre-analytical variability, isolation heterogeneity, and uncertain cellular origin—limit reproducibility; recommended solutions include standardized workflows, carrier-and cell type-specific enrichment, multimodal integration with proteomics/metabolomics and neuroimaging, and large, longitudinal validation studies. We synthesize mechanistic and clinical evidence for exRNA utility in early detection, prognosis, and therapeutic targeting and outline a roadmap to translate exRNA findings into robust clinical assays and interventions for neurodegenerative and brain disorders.  \nKeywords: extracellular RNA; extracellular vesicles; blood–brain barrier; neurodegeneration; biomarkers; neuroinflammation; mitochondria  \n1. Introduction  \nExtracellular RNAs (exRNAs) encompass a diverse set of RNA species released by cells into the extracellular milieu and detectable in biofluids such as blood, cerebrospinal fluid (CSF), saliva, and urine [1–3] . Major classes include microRNAs (miRNAs, ~22 nucleotides), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), mitochondrial RNAs (mtRNAs), and messenger RNAs (mRNAs) . In bodily fluids, these molecules are often protected. For example, quantitative profiling indicates that more than 90% of circulating miRNAs are associated with Argonaute-2 (Ago2) or other RNA-binding proteins, whereas less than 10% are vesicle-associated [4] . This selective protection not only prolongs RNA half-life but also suggests that exRNAs are biologically meaningful rather than random degradation products [4–6] . Stabilized carriers likely protect them from abundant nucleasesand enable systemic transport—principally membrane-bound extracellular vesicles (EVs),  \nRNA-binding protein complexes, and lipoprotein particles [3–6] . There are two types of EVs: exosomes are generated from the endosomal system and released upon multivesicular body fusion with the plasma membrane [7–10], whereas microvesicles are formed by the direct outward budding and fission of the plasma membrane [8,9,11] . Here, we provide only the general biogenetic context of these vesicles, as detailed subclass distinctions and atypical biogenesis routes are beyond the scope of this review.  \nExperimental work has established two complementary roles for exRNAs. Firs","cbCaivncmtrvelCl","https://ap.wps.com/l/cbCaivncmtrvelCl","pdf",2998309,41,"English","# Introduction\n## Extracellular RNAs in biofluids and carrier protection\n## Two complementary roles: reporting and functional effectors\n## Rationale for early detection in neurodegenerative disease","[{\"question\":\"What makes extracellular RNAs suitable for early neurodegeneration biomarkers?\",\"answer\":\"ExRNAs are detectable in biofluids and remain stable through protection by carriers such as extracellular vesicles, RNA-binding proteins, and lipoproteins. Early transcriptional and metabolic disturbances—including mitochondrial dysfunction and oxidative stress—often precede overt pathology, enabling early detection.\"},{\"question\":\"How do exRNAs act beyond biomarker reporting?\",\"answer\":\"Mechanistic studies show selective packaging and delivery: transferred mRNAs can be translated, and EV-shuttled miRNAs can repress target mRNAs. This supports the idea that exRNAs can actively influence recipient cell gene-expression networks.\"},{\"question\":\"Why is reproducibility difficult in exRNA studies?\",\"answer\":\"Major limitations include pre-analytical variability, isolation heterogeneity, and uncertain cellular origin of exRNAs. These factors can hinder consistent detection and comparison across studies.\"}]","Extracellular RNAs as Messengers and Early Biomarkers in Neurodegeneration - review | PDF",1790762472,103]