Extracellular vesicle-integrated brain organoid-on-a-chip systems for neuroimmune communication and precision therapy in viral encephalitis

Abstract

Viral encephalitis causes substantial neurological morbidity and mortality through the combined effects of direct viral injury, blood–brain barrier (BBB) dysfunction, and dysregulated communication among neural, vascular, and immune cells. Extracellular vesicles (EVs) are increasingly recognized as mediators of this communication because they transfer proteins, lipids, viral constituents, cytokine-related signals, and regulatory RNAs between neurons, astrocytes, microglia, endothelial cells, and peripheral immune cells. Depending on their cellular origin and cargo, EVs may support antiviral defense or propagate viral dissemination, neuroinflammation, barrier injury, and persistent neurological sequelae. This narrative review synthesizes evidence for an EV–neuroimmune axis in viral encephalitis and evaluates how that evidence could inform the design of brain organoid-on-a-chip (BOoC) models. The review distinguishes established findings from a proposed integrated platform that would combine patient-derived brain organoids, a BBB-interposed vascular and immune compartment, real-time EV tracking, transendothelial electrical resistance and electrophysiological sensing, and multi-omics analysis. Existing studies support several individual components of this framework, but a fully integrated EV–BOoC system with closed-loop artificial intelligence (AI) control has not yet been demonstrated for viral encephalitis. Accordingly, digital twins, autonomous treatment optimization, and patient-specific clinical prediction are presented as future research directions rather than current capabilities. This calibrated framework identifies measurable design requirements, evidence gaps, and translational priorities for mechanistic studies, biomarker discovery, and precision therapeutic screening.