Profiling small extracellular vesicles microRNAs and their expressions in EVs-depleted plasma as biomarkers for distinguishing schizophrenia

In schizophrenia (SZ), significant alterations in microRNAs (miRNAs) regulation and the underlying mechanisms of post-transcriptional modification have been observed. Extracellular vesicles (EVs) encapsulate miRNAs, protecting them from degradation and enabling long-range intercellular communication. While profiling sEV-derived miRNAs (sEV-miRNAs) is essential for understanding sEV-mediated signaling, examining sEV-associated miRNAs in EVs-depleted (dEV) plasma is equally important for evaluating their selectivity and potential roles in systemic physiological regulation. To investigate the hypothesis that specific miRNAs are selectively enriched in small EVs (sEVs), we compared sEV-miRNAs expression profiles between SZ patients and nonpsychotic controls (NC). We then conducted a side-by-side comparison of candidate sEV-associated miRNA expressions in dEV plasma. In the screening set (N = 24), five aberrantly expressed sEV-miRNAs (miR-23a, miR-103a, miR-182, miR-450b, and miR-4433b) were selected for further validation. In the validation set (N = 139), miR-23a, miR-103a, and miR-450b were highly expressed in SZ patients' sEVs, they were less expressed in dEV plasma. This could indicate miRNAs may play various roles in signal transduction based on their origin and distribution. An optimal marker panel (sEV-miR-103a, sEV-miR-450b, and dEV-miR-450b) was established to differentiate SZ patients from NC, yielding an area under the curve (AUC) of 0.988 and an accuracy of 0.935. In the 10-fold cross-validation model, AUC was 0.930, and accuracy was 0.887. Enrichment analysis showed that dysregulated sEV-associated miRNAs are involved in neurobiological and immune pathways in SZ. These findings support a link between SZ and altered posttranscriptional regulation mediated by specific sEV-miRNAs, highlighting their potential as therapeutic targets.