Extracellular Vesicles as Mediators and Biomarkers in Aging and Neurodegenerative Disorders: From Molecular Cargo to Clinical Translation

Extracellular vesicles (EVs), including exosomes, microvesicles, apoptotic bodies, and many other EV subtypes, have emerged as critical mediators of intercellular communication in both physiological and pathological conditions. These membrane-bound nanoparticles transport a broad repertoire of molecular cargo - including proteins, DNA, multiple RNA species, lipids, and metabolites - between cells, thereby modulating signaling pathways, cellular phenotypes, and tissue homeostasis. In neurological and neurodegenerative disorders such as Alzheimer's disease and related tauopathies, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), EVs play complex and multifaceted roles. In addition, their roles in aging, the primary risk factor of most of these diseases, have only recently started to be explored.EVs have been proposed to act as carriers of misfolded proteins, disease-associated signals, and inflammatory mediators, potentially contributing to the propagation or modulation of pathology, but they can also mediate neuroprotective functions by modulating immune responses, supporting tissue repair mechanisms, facilitating clearance of toxic molecules, and maintaining cellular homeostasis. This dual nature makes EVs both promising sources of disease-relevant biomarkers and attractive therapeutic targets.Importantly, EVs are generated not only by eukaryotic cells but also by bacteria, being typically 30–150 nm in size and carrying RNAs, lipids, carbohydrates, and proteins reflective of their source. While human EVs act locally and only a minority enter the bloodstream, a substantial fraction of intestinal microbiotal bacterial EVs may enter circulation and distribute broadly, including to the CNS.The ability of certain EV populations to cross the blood-brain barrier and their presence in accessible biofluids - including blood, cerebrospinal fluid, tears, saliva, and urine - positions EVs as ideal candidates for liquid biopsy approaches in neurology. Their molecular cargo provides a dynamic snapshot of ongoing cellular processes within the brain, offering unprecedented opportunities for minimally invasive monitoring of disease states. Recent advances in isolation techniques, multi-omics profiling, and single-vesicle analysis are revealing new insights into EV heterogeneity, molecular signatures, and functional roles. Furthermore, engineered EVs are being developed as next-generation drug delivery vehicles and as modulators of neuroinflammation and immune responses, opening transformative avenues for precision medicine.Despite these remarkable advances, significant challenges continue to hinder the translation of EV research into clinical practice. Key obstacles include the lack of standardized reproducible protocols for EV isolation, characterization, and quantification; an incomplete understanding of tissue- and cell-type-specific EV populations, their biogenesis, trafficking dynamics, and target cell interactions; and limited clinical validation of EV-based biomarkers and therapies in large, well-characterized patient cohorts. Additionally, distinguishing disease-driving EVs from those with protective or homeostatic functions remains a significant challenge. Addressing these barriers requires multidisciplinary studies that integrate molecular and cellular neuroscience, advanced neuroimaging modalities, multi-omics technologies, artificial intelligence-driven data analysis, computational modeling, and rigorous clinical evaluation to fully realize the diagnostic and therapeutic potential of EVs in neurodegenerative disorders.This Research Topic aims to bring together clinicians, neuroscientists, cell biologists, bioengineers, and data scientists to advance our understanding of extracellular particles in aging and neurodegenerative diseases and accelerate their development as accessible biomarkers and effective therapeutic tools within personalized and precision medicine frameworks.We welcome contributions that span basic, translational, and clinical research, including in vitro and in vivo disease models, human patient cohorts, and computational approaches. Submissions may address, but are not limited to, the following themes:● EVs in Neuroplasticity and Recovery: Exploring the role of EVs in neural repair, regeneration, and adaptive responses following injury or therapeutic intervention.● EV-Mediated Mechanisms of Physiological Aging and Disease: Investigating how EVs contribute to neuroinflammation, synaptic dysfunction, cellular senescence and disease progression in neurodegenerative disorders, as well as to the more subtle changes associated with physiological aging.● EVs in body-brain communication: Studying the roles of EVs as mediators of inflammatory and pathological signals from the periphery to the brain to contribute to brain aging and neurodegeneration, e.g. gut-to-brain axis.● EVs and the extracellular matrix: Exploring how EVs interact with the brain extracellular matrix (ECM) in brain health and disease, and the possible effects on neurons and the synapse.● Cross-Disorder Comparisons: Comparative studies of EV signatures across different neurodegenerative conditions, or between aging and neurodegeneration, to identify shared and distinct mechanisms.● Biomarker Discovery and Validation: Identifying EV-associated molecular signatures (DNA, RNAs, proteins, lipids, metabolites) for early diagnosis, patient stratification, and monitoring treatment response.● AI and Computational Approaches: Machine learning models for EV corona and cargo analysis, predictive biomarker panels, and patient stratification based on EV profiles.● Technological and Methodological Innovations in EP/EV Isolation and Characterization: Novel or improved methods for EP/EV isolation, purification, and multi-omics analysis, including single-vesicle techniques and spatial profiling.● Standardization and Translation: Addressing methodological challenges and establishing reproducible protocols for clinical implementation of EV-based diagnostics and therapeutics.● Therapeutic Applications: Engineering EVs for targeted drug delivery, gene therapy, or immunomodulation in neurological diseases and the aging process.We encourage a wide range of submissions, including Original Research and Clinical Trials, Reviews, Mini Reviews, Perspectives, Methods, Data Reports, Technology and Code, Hypothesis and Theory, and Case Reports.Through these investigations, this Research Topic aims to refine aging/disease models, accelerate biomarker discovery and validation, and advance EV-based diagnostics and therapeutics, ultimately promoting healthy aging and enabling earlier diagnosis and personalized treatment to improve outcomes for patients living with neurodegenerative disorders. Topic editors: Alice Maria Giani, Martina Gabrielli, Edward J Goetzl, Yang You Source: https://www.frontiersin.org/research-topics/76320/extracellular-vesicles-as-mediators-and-biomarkers-in-aging-and-neurodegenerative-disorders-from-molecular-cargo-to-clinical-translation