Adult T-cell leukemia/lymphoma (ATLL) is an aggressive, clonal malignancy of mature T cells caused by human T-cell leukemia virus type 1. Although it is a rare tumor type, it serves as an excellent model of a virus driven process that transforms cells and engenders a highly malignant tumor that is extraordinarily difficult to treat. The viral transcriptional transactivator (Tax) in the HTLV-1 genome directly promotes tumorigenesis, and Tax-induced oncogenesis depends on its ability to constitutively activate NF-κB signaling. Accordingly, we developed and evaluated a nano-delivery system that simultaneously inhibits both canonical (p65) and noncanonical (p100) NF-κB signaling pathways locally in tumors after systemic administration. Our results demonstrate that siRNA is delivered rapidly to ATLL tumors after either i.p. or i.v. injection. The siRNA treatment significantly reduced both p65 and p100 mRNA and protein expression. Anti-NF-κB nanotherapy significantly inhibited tumor growth in two distinct tumor models in mice: a spontaneous Tax-driven tumor model, and a Tax tumor cell transplant model. Moreover, siRNA nanotherapy sensitized late-stage ATLL tumors to the conventional chemotherapeutic agent etoposide, indicating a pleiotropic benefit for localized siRNA nanotherapeutics.