| Summary: | Edible plants have been widely used in traditional therapeutics because of the biological activities of their natural ingredients, including anticancer, antioxidant, and anti-inflammatory properties. Plant sap contains such medicinal substances and their secondary metabolites provide unique chemical structures that contribute to their therapeutic efficacy. Plant extracts are known to contain a variety of extracellular vesicles (EVs) but the effects of such EVs on various cancers have not been investigated. Here, we extracted EVs from four plants—<i>Dendropanax morbifera</i>, <i>Pinus densiflora</i>, <i>Thuja occidentalis,</i> and <i>Chamaecyparis obtusa</i>—that are known to have cytotoxic effects. We evaluated the cytotoxic effects of these EVs by assessing their ability to selectively reduce the viability of various tumor cell types compared with normal cells and low metastatic cells. EVs from <i>D. morbifera</i> and <i>P. densiflora</i> sap showed strong cytotoxic effects on tumor cells, whereas those from <i>T. occidentalis</i> and <i>C. obtusa</i> had no significant effect on any tumor cell types. We also identified synergistic effect of EVs from <i>D. morbifera</i> and <i>P. densiflora</i> saps on breast and skin tumor cells and established optimized treatment concentrations. Our findings suggest these EVs from plant sap as new candidates for cancer treatment.
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