Opinion Brain-Liquid biopsy and extracellular vesicles: Toward neuroimmune and neurovascular precision in psychosis spectrum disorders, 2026, Altunsu & Lizano

[SNT Gatchaman]

Brain-Liquid biopsy and extracellular vesicles: Toward neuroimmune and neurovascular precision in psychosis spectrum disorders
Altunsu; Lizano

No abstract.

Web | DOI | Brain, Behavior, and Immunity | Paywall

 

[SNT Gatchaman]

Psychosis spectrum disorders remain defined almost entirely by clinical observation, despite decades of evidence demonstrating the profound neurobiological complexity that drives their onset, progression, and heterogeneity. Epidemiologic, genetic, and neuropathologic studies consistently implicate disruptions in neuroimmune signaling, synaptic function, metabolic pathways, and neurovascular regulation engaging diverse brain cell types including neurons, glia, endothelial cells, ependymal cells, immune cells, and neural progenitors. Yet, psychiatric diagnosis, prognostication, and treatment selection continue to rely primarily on observable symptoms, behavior, cognition, and functioning.

Early biomarker efforts in psychosis have largely focused on a limited number of peripheral bloodbased measures such as cytokines and growth factors; however, these approaches have lacked the cellular specificity, mechanistic resolution, and longitudinal stability required for clinical utility. This limitation is particularly problematic given growing recognition that immune-brain interactions and vascular dysfunction play central roles in psychosis pathophysiology. The emergence of liquid biopsy approaches leveraging extracellular vesicles (EVs) offers a promising strategy to address this long-standing gap.

Immune-brain processes remain largely invisible to routine clinical assessment but may be reflected in EV cargo. EVs are nanoscale, membrane-bound particles released by virtually all cell types, including neuronal, glial, endothelial, immune, and progenitor cells. Importantly, EVs can cross the blood-brain barrier and circulate in peripheral blood, carrying proteins, lipids, and nucleic acids that mirror the physiological and pathological states of their cells of origin. In doing so, EVs provide a biologically grounded interface between central nervous system processes and peripheral biospecimens, mapping directly onto pathways implicated in psychosis spectrum disorders, as well as other psychiatric disorders. Psychosis spectrum disorders may be particularly well suited to EV-based liquid biopsy approaches because they are characterized by dynamic neuroimmune activation, complement-mediated synaptic remodeling, and increasing evidence of blood-brain barrier instability. These processes are temporally fluctuating, stage dependent, and biologically heterogeneous, making them difficult to capture using static clinical assessments or single-analyte peripheral biomarkers.

 

[SNT Gatchaman]

Beyond their diagnostic value, EVs should be conceptualized not merely as passive reporters of disease state but as active biological mediators capable of shaping neuroimmune and neurovascular signaling. EV cargo can directly influence recipient cell function, modulating inflammatory cascades, synaptic pruning, metabolic regulation, and blood-brain barrier integrity. This distinction is particularly relevant in psychosis spectrum disorders, where converging evidence points to immune dysregulation and endothelial dysfunction as contributors to disease onset and progression.

Emerging work in neurology and neuroinflammation further suggests that exosomes, a major subclass of EVs, may serve as viable therapeutic delivery vehicles for targeting immune and vascular pathways within the central nervous system. Engineered exosomes can be loaded with regulatory RNAs or proteins and delivered to the brain, providing proof of principle for modulating disease-relevant pathways. Although such approaches remain largely preclinical, they highlight the potential for EV platforms to support a theranostic framework in which biological signatures guide intervention and treatment response is monitored using the same molecular systems.

By anchoring diagnosis, stratification, and monitoring in underlying neuroimmune and neurovascular biology, EV-based liquid biopsy offers a scalable and mechanistically informative tool that has long been absent from psychiatric practice. Psychiatry now stands at an inflection point, and the integration of extracellular vesicle-based brain liquid biopsy into research pipelines represents a critical step toward biologically informed and precision-oriented care.

The future of psychiatry likely lies in the integration of structured clinical evaluation with scalable molecular profiling, enabling a precision-oriented framework that bridges symptom expression and underlying pathophysiology.