The Dual Role of Exosome-Mediated Central-Peripheral Immune Dialogue in Amyotrophic Lateral Sclerosis-Associated Neuroinflammation.

Objective: Amyotrophic lateral sclerosis (ALS) is increasingly viewed as a multisystem disorder in which central-peripheral immune communication may modify neuroinflammation. Exosomes, an endosome-derived subset of extracellular vesicles (EVs), have been proposed as mediators of this communication, but the strength and disease specificity of the evidence require critical evaluation. Methods: PubMed/MEDLINE, Web of Science Core Collection, and Scopus were searched from database inception to July 20, 2026, with supplementary citation tracking through Google Scholar and reference lists. Evidence was categorized as human ALS evidence, ALS-specific cellular or animal evidence, evidence from non-ALS neuroinflammatory models, or review-level background evidence. Results: Human studies have identified ALS-associated proteins and altered miRNA profiles in circulating EV-containing preparations, but their cellular origin, direction of transfer, and causal relevance remain uncertain. ALS-specific cellular and animal models support the possibility that EVs participate in intercellular protein transfer and modify glial inflammatory, phagocytic, antioxidant, and trophic responses. Some proposed mechanisms, including miR-216a-5p-mediated microglial regulation, are derived mainly from other neurological injury models and should be considered hypothesis-generating. Single-cell studies further indicate that ALS microglia occupy heterogeneous and overlapping states; therefore, M1/M2 terminology is used only as a simplified descriptive framework. Circulating EV cargo remains under investigation as a biomarker source, whereas the additional value of EV-associated neurofilament light chain and the diagnostic utility of TDP-43, SOD1, or miRNAs require independent validation. Therapeutic evidence remains predominantly preclinical, with only small, early, non-confirmatory human studies. Conclusion: EVs may participate in central-peripheral immune communication in ALS, but their causal role, cellular origin, in vivo trafficking, and clinical utility remain incompletely established. Standardized methods and rigorous mechanistic and clinical validation are required before EV-based biomarkers or therapies can be translated into practice.