Extracellular vesicle miRNAs, NOS/NO homeostasis, and NLRP3 inflammasome signaling in schizophrenia-related cognitive impairment: a mechanistic review and testable hypothesis

Cognitive impairment is a major determinant of poor functional recovery in schizophrenia, but the molecular events connecting neuroimmune disturbance, redox imbalance, and synaptic dysfunction remain incompletely understood. Studies in patients have reported altered extracellular vesicle microRNA (EV-miRNA) profiles, abnormalities in nitric oxide synthase/nitric oxide (NOS/NO)-related markers, and altered or increased microglial expression of NLRP3 inflammasome-associated proteins. These findings point to possible convergence among EV-mediated signaling, redox regulation, and inflammasome activity, yet they do not define a continuous causal pathway. This review examines evidence from patient studies, patient-derived and schizophrenia-related models, and mechanistic work in other disease contexts to assess a putative EV-miRNA–inflammatory transcriptional network–NOS/NO–NLRP3–synaptic/cognitive impairment framework. We emphasize several evidentiary boundaries: EV-miRNA expression changes should be distinguished from functional intercellular delivery, predicted targets should not be treated as validated mechanisms, and peripheral molecular associations cannot by themselves establish pyroptosis in the brain. The framework also highlights the context dependence of NO-related effects, particularly their reliance on the redox microenvironment, and separates cytokine maturation and release, GSDMD-mediated pore formation, and pyroptotic cell death as related but distinct downstream events. Future studies should determine whether source-defined EV-miRNAs directly regulate NOS/NLRP3 signaling, whether these molecular changes precede longitudinal cognitive decline, and whether intervention or rescue experiments can demonstrate causal links across the pathway. Integrating source-resolved EV profiling, multi-omics analysis, and clinical follow-up may clarify whether combined molecular indicators can support cognitive stratification and risk prediction in schizophrenia.