Cross-cohort exosomal miRNA profiling identifies a robust Parkinson’s disease signature with multi-omics evidence for mitochondrial and immune pathology

Parkinson’s disease (PD) lacks reliable non-invasive biomarkers for early diagnosis. Peripheral blood-derived exosomes, which carry central nervous system (CNS)-derived cargo across the blood-brain barrier, represent a promising liquid biopsy platform. Here, we performed integrated miRNA and proteomic profiling of blood exosomes, leveraging multiple public datasets for biomarker discovery and an in-house cohort for independent validation. Consensus feature selection integrating five methods identified robust biomarker panels evaluated by four classification models. A 69-miRNA consensus signature achieved strong PD classification performance, with Random Forest demonstrating the best generalization (AUC = 0.952), whereas the 63-protein proteomics signature showed limited cross-study reproducibility (best AUC = 0.611), attributable to inter-platform heterogeneity. Tissue origin profiling revealed that signature miRNAs derive from both CNS and peripheral immune compartments. Functional enrichment across omics layers consistently highlighted mitochondrial energetics failure and suppression of complement and coagulation cascades. Deconvolution and independent single-cell RNA sequencing validation traced exosomal origins to a distinct immune-metabolic axis involving B cells and CD4 + T cells. Our study identifies a robust exosomal miRNA signature for PD classification and reveals the convergence of mitochondrial dysfunction and peripheral immune dysregulation as core pathological features, establishing a foundation for exosome-based liquid biopsy and mechanistic biomarker development.