Major findings of our study are that (i) the targeting antigen CD30 is present on l-EVs and s-EVs from L540 cells, (ii) such EVs bind to both, the immunotoxin BV and the DLBCL cells, (iii) EVs are taken up by target cells, and (iv) dependent on BV and CD30+ EVs, such BV-loaded EVs also damage CD30– DLBCL cells dependent on BV and CD30+ EVs (Figure 4). Here, TNFRSF8 is linked to diffuse large B-cell lymphoma.