Long-term liver infection represents a conserved parasitism of E. granulosus in the intermediate hosts. However, mechanisms of mediators driving liver parasitism remain unclear. Here, we elucidated the characteristics and composition of small extracellular vesicles originating from E. granulosus. Further, we unveiled target capacities, regulatory roles, and pathogenic properties of protoscoleces-derived small extracellular vesicles (PSC-sEV), which displayed a key mediator contributing to the pathogenesis of E. granulosus. By utilizing single-cell RNA-seq, we identified heterogeneity in the cell subpopulations (endothelial cells, myeloid cells, NK and T cells) regulated by PSC-sEV during liver infection of E. granulosus. Finally, we proposed a potential mechanism for achieving parasite-host communication through selective internalization of PSC-sEV in target cells and manipulation of cellular functions via miRNA-TF-mRNA networks. Our work underscores intercellular crosstalk landscapes of E. granulosus and host, highlighting the necessity of targeting PSC for therapeutic intervention and potential of PSC-sEV as a diagnostic biomarker.