Small extracellular vesicles (sEVs) are nanosized vesicles. Death receptor 5 (DR5) mediates extrinsic apoptosis. We engineer DR5 agonistic single-chain variable fragment (scFv) expression on the surface of sEVs derived from natural killer cells. PDGFR transmembrane domain delivers DR5-scFvs to the surface of sEVs. DR5-scFv sEVs rapidly induce apoptosis of different types of DR5+ cancer cells, myeloid-derived suppressor cells (MDSCs), and cancer-associated fibroblasts (CAFs). DR5-scFv sEVs migrate specifically to DR5+ tumors in vitro and in vivo. Systemic delivery of DR5-scFv sEVs significantly inhibits the growth of DR5+ melanoma, liver cancer, and breast cancer and prolongs mouse life span without significant toxicity. DR5-scFv sEVs are significantly more efficacious than DR5 antibodies in vivo. In organotypic patient-derived melanoma slice cultures, DR5-scFv sEVs effectively inhibit melanoma cells and MDSCs and activate CD8+ T cells. Our studies demonstrate that DR5-scFv sEVs can inhibit tumor growth by targeting tumor cells and immunosuppressive stromal cells in the TME.