Circulating Exosomes Drive Persistent Neuronal Dysfunction in Post‐Herpetic Neuralgia Patients

OBJECTIVE: Post-herpetic neuralgia (PHN) is a debilitating chronic pain condition persisting beyond 3 months after herpes zoster (HZ), yet the mechanisms driving the transition from acute viral injury to chronic neuropathic pain remain poorly characterized. We tested whether circulating exosomes are sufficient to drive sensory neuron dysfunction independent of direct varicella zoster virus infection. METHODS: Human nociceptive neurons were either directly infected with varicella zoster virus or exposed to exosomes isolated from sera of control individuals, patients with acute HZ, or patients with post-herpetic neuralgia. Neuronal responses were assessed by bulk RNA sequencing (RNA-seq), gene set enrichment analysis, multiplex cytokine and matrix metalloproteinase-9 immunoassays, lactate dehydrogenase cytotoxicity assays, live-cell imaging of neurite dynamics, and mass spectrometry-based proteomic profiling of exosome cargo. RESULTS: Direct viral infection induced a pro-inflammatory, metabolically active neuronal state with increased interleukin-8 and interleukin-13 secretion and elevated extracellular matrix remodeling pathways. PHN exosomes recapitulated and amplified this phenotype in uninfected neurons, suppressing neurite extension gene networks through predicted inhibition of the RNA-binding protein ELAVL4, functionally impairing neurite outgrowth, and inducing matrix metalloproteinase-9 secretion without cytotoxicity. Proteomic profiling identified complement C3b and HSPA5 enriched on PHN exosomes. Canonical nociceptive ion channels were downregulated whereas substance P was upregulated, indicating a shift toward neuropeptide-mediated signaling. INTERPRETATION: These findings establish a failure-to-resolve model in which persistent exosome-mediated signaling sustains maladaptive neuronal remodeling after viral clearance, identifying circulating exosome cargo as previously unreported mechanistic contributors to PHN pathogenesis and potential therapeutic targets. ANN NEUROL 2026.