Abstract
Extracellular RNAs are released from cells and circulate stably in biofluids such as blood, cerebrospinal fluid, saliva, and urine via carriers including extracellular vesicles, RNA-binding 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.