Current treatment for glioblastoma multiforme (GBM) fails to address its highly infiltrative nature; treatment often leaves behind microscopic neoplastic satellites, resulting in eventual tumor recurrence. Here we report polymeric nanoparticle-engineered human adipose-derived stem cells (hADSCs) overexpressing the cancer-specific TNF-related apoptosis-inducing ligand for targeting and eradicating glioblastoma cells. Engineered hADSCs exhibited long-range directional migration toward tumor in patient-derived GBM orthotropic xenografts and showed significant inhibition of tumor growth and extension of animal survival. Repetitive injection further prolonged animal survival compared with single injection. Together, our data suggest that nanoparticle-engineered hADSCs exhibit the therapeutically relevant behavior of “seek-and-destroy” tumortropic migration, and may offer a promising therapy for substantial enhancement of GBM treatment.