2026 ECNP Congress

PS04-4212

Schizophrenia-derived extracellular vesicles drive microglial alterations: neurodevelopmental implications and potential for targeted drug delivery

Licia Vellucci — A. Menale, D. Formisano, A. Nasti, A. Barone, F. Iasevoli, E. Torino, A. de Bartolomeis · University Medical School of Naples Federico II, Department of Neuroscience- Reproductive Sciences- and Dentistry, Naples, Italy

2026 ECNP Congress

Background

Schizophrenia is a chronic and severe psychiatric disorder affecting approximately 1% of the global population and is increasingly conceptualized as a disorder of disrupted neurodevelopment and brain connectivity, in which glial cells play a central regulatory role [1;2;3]. Extracellular vesicles (EVs) have recently emerged as key mediators of intercellular communication within the central nervous system, representing a potential mechanism for the propagation of glial dysfunction and neuroinflammatory signals in schizophrenia [4]. In addition to their role in pathophysiology, EVs are also being investigated as mediators of targeted drug delivery, with the potential to transport pharmacological agents to specific brain regions, thereby enhancing therapeutic precision and efficacy [5].

Aims

In this context, the present study aims to assess whether EVs isolated from patients with schizophrenia induce morphological changes in developing microglial cells, thereby providing insight into early pathogenic mechanisms linking peripheral signals to central neuroimmune alterations.

Methods

EVs were isolated from peripheral blood samples collected from patients with schizophrenia and matched healthy controls by differential ultracentrifugation. Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) and the PANSS Autism Severity Score (PAUSS). Neurological vulnerability was evaluated using the Neurological Evaluation Scale (NES), while cognition was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS). The isolated EVs underwent comprehensive characterization of their biophysical and functional properties. Nanoparticle Tracking Analysis and zeta potential measurements were employed to assess particle size distribution, concentration, and surface charge. To evaluate the functional impact of EVs, BV2 microglial cells were monitored using the xCELLigence real-time cell analysis system, allowing for dynamic, label-free tracking of cell viability and morphological changes post-exposure. Furthermore, these EVs are being evaluated as potential drug delivery systems for antipsychotics through the implementation of novel cargo-loading strategies, where identifying specific biomarkers remains a critical step in evaluating the biological signature of both loaded and unloaded EVs.

Results

The isolation protocol successfully yielded EVs from both schizophrenia patients and healthy controls, exhibiting biophysical profiles (size, concentration, and surface charge) consistent with small EV populations (sEVs). Functional assays using a high throughput screening real time live cell imaging system revealed that both control and patient-derived EVs induced dose-dependent alterations in BV2 cellular impedance. Building on these observations, current analyses are investigating the proteomic and transcriptomic signaling pathways to elucidate how these vesicles contribute to systemic inflammation and to further validate their efficacy as targeted vehicles for precision antipsychotic therapy.

Conclusions

Schizophrenia-derived EVs exert active, cargo-dependent effects on microglial cells, supporting their role as mediators of dysregulated intercellular communication. These findings align with neurodevelopmental models implicating altered microglial function in aberrant synaptic pruning and network maturation. EVs may represent a mechanistic bridge between peripheral signals and central neuroimmune dysfunction. Their influence on microglia also suggests a potential interaction with the immunomodulatory effects of antipsychotics. Finally, EVs emerge as promising tools for targeted drug delivery, enabling more precise and effective therapeutic strategies.

References

  1. Correll, C.U.; Ismail, Z.; McIntyre, R.S.; Rafeyan, R.; Thase, M.E. Patient Functioning, Life Engagement, and Treatment Goals in Schizophrenia. J. Clin. Psychiatry 2022, 83, Lu21112ah2.
  2. McGrath, J.J., Feron, F.P., Burne, T.H., Mackay-Sim, A., Eyles, D.W., 2003. The neurodevelopmental hypothesis of schizophrenia: a review of recent developments. Ann. Med. 35 (2), 86–93.
  3. Nath, M., Wong, T.P., Srivastava, L.K., 2021. Neurodevelopmental insights into circuit dysconnectivity in schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 104, 110047.
  4. Gangachannaiah, S., Shenoy, S., Upadhya, D. et al. Potential of extracellular vesicle cargo as molecular signals in Schizophrenia: a scoping review. Schizophr 11, 17 (2025).
  5. Kumar, M.A., Baba, S.K., Sadida, H.Q. et al. Extracellular vesicles as tools and targets in therapy for diseases. Sig Transduct Target Ther 9, 27 (2024).