biostudies-literatureSultana HNational Institute of Allergy and Infectious DiseasesNIAID NIH HHSNational Institutes of Health110391https://www.ebi.ac.uk/biostudies/studies/S-EPMC11301069biostudies-literatureUnknown27(8)Exosomes/extracellular vesicles (EVs) are essential for the successful transmission of flaviviruses from vector to vertebrate host. Arthropod-EVs are envisioned as important target for blocking the transmission of vector-borne viral diseases. In this study, we show that the selective inhibition of EVs secretion by sphingomyelinase inhibitor, GW4869 significantly reduces vector efficiency and competence in acquiring and transmitting tick-borne flaviviruses. We show that GW4869 reduces EVs release from Langat Virus (LGTV)-infected <i>Ixodes scapularis</i> adult tick salivary glands (SGs). GW4869 treatment showed reduced dissemination of LGTV in SGs and other tissues within ticks. Decreased release of SG-EVs directly correlated with reduced tick blood-feeding efficiency, engorgement weights, iScienceGW4869 inhibitor affects vector competence and tick-borne flavivirus acquisition and transmission by blocking exosome secretion.PMC11301069R01 AI141790R01AI141790Ahmed WNeelakanta GSultana HfalseGW4869 inhibitor affects vector competence and tick-borne flavivirus acquisition and transmission by blocking exosome secretion.Exosomes/extracellular vesicles (EVs) are essential for the successful transmission of flaviviruses from vector to vertebrate host. Arthropod-EVs are envisioned as important target for blocking the transmission of vector-borne viral diseases. In this study, we show that the selective inhibition of EVs secretion by sphingomyelinase inhibitor, GW4869 significantly reduces vector efficiency and competence in acquiring and transmitting tick-borne flaviviruses. We show that GW4869 reduces EVs release from Langat Virus (LGTV)-infected <i>Ixodes scapularis</i> adult tick salivary glands (SGs). GW4869 treatment showed reduced dissemination of LGTV in SGs and other tissues within ticks. Decreased release of SG-EVs directly correlated with reduced tick blood-feeding efficiency, engorgement weights, 2024-01-01T00:00:00Z2024 Aug2026-06-04T05:32:29.64Z2025-04-04T00:39:06.469ZS-EPMC113010693910871110.1016/j.isci.2024.110391