Penumbra-derived small extracellular vesicles carry pathogenic RNA driving remote damage after cortical infarction.

Small extracellular vesicles efficiently transport pathological RNAs in ischaemic stroke, but whether penumbral hypoxia-induced extracellular vesicles deliver pathogenic cargo to remote regions, impacting acute ischaemic stroke outcomes, remains unclear. Using a focal ischaemia mouse model, we isolated brain-derived extracellular vesicles (BDEVs) from the cortical penumbra and determined their pathological impact on synaptically connected remote regions. In vitro, penumbral BDEVs (PEVs) exacerbated recipient neuronal damage, intensifying apoptosis and dendritic injury during oxygen-glucose deprivation/reoxygenation. In vivo tracing confirmed PEV transport via anatomical projections to remote thalamic neurons, where internalization triggered synaptic loss and apoptosis in distal thalamic nuclei. Mechanistically, PEVs delivered the penumbra-specific circular RNA CircOGDH through trans-synaptic delivery to connected thalamic neurons, directly inducing synaptic and neuronal injury. Critically, cortical CircOGDH knockdown abolished thalamic CircOGDH accumulation and reversed neuronal loss and synaptic impairment, confirming its causal role in secondary damage. Transcriptomics further revealed PEV enrichment in RNAs dysregulating synaptic and axonal pathways. Thus, we open a new view PEVs initiated a thalamus pathogenic pathway where BDEVs deliver CircOGDH and functional RNAs to drive non-infarcted region degeneration. This redefines remote post-stroke injury as an active RNA trafficking process, highlighting therapeutic opportunities for intercepting extracellular vesicle-mediated trans-synaptic pathology.