Pomelo-derived exosomes suppress vesicular stomatitis virus infection through GSK3β dependent regulation of innate immune signaling.

RNA virus infection triggers robust innate immune activation and inflammatory injury. Using vesicular stomatitis virus (VSV) as a model, we investigated the antiviral and immunomodulatory effects of pomelo-derived extracellular vesicles (EVPomelo). Among multiple plant vesicles screened, EVPomelo exhibited the strongest anti-VSV activity in vitro and in vivo. LC-MS analysis identified penicillic acid (PA) as an important endogenous bioactive component. Mechanistically, EVPomelo suppressed viral replication and reduced IFN-β and IL-6 production, accompanied by the inhibition of the signal transducer and activator of transcription 1 (STAT1) activation and decreased ISG15 transcription. Functional evidence suggests that these effects may be associated with the modulation of glycogen synthase kinase 3β (GSK3β)-dependent signaling, to which PA may contribute. Sodium alginate (SA) encapsulation further improved in vivo retention and sustained release. Collectively, EVPomelo exert antiviral effects by suppressing virus-induced excessive inflammatory response. The underlying mechanism may be associated with the GSK3β/STAT1-mediated innate immune signaling pathway. These findings verify that EVPomelo possesses promising antiviral potential for further development.