Using in vivo test systems that faithfully model advanced-stage ovarian cancer, metastatic melanoma, and glioblastoma, we establish that serial administration of IRF5/IKKβ-encoding NPs (via an intraperitoneal route for ovarian cancer, and injected intravenously to treat melanoma lung metastases or glioblastoma) substantially reduce tumor progression and, in some animals, even clear the disease. Here, IKBKB is linked to melanoma.