The systematic use of therapeutic short-interfering RNAs (siRNAs) is limited by their very short half-life in the blood and their lack of tumor-targeting capabilities. Although packaging siRNAs into nanoparticles, such as liposomes or cationic polymers, can mitigate some of these shortcomings, it is difficult to produce a homogenous collection of nanoparticles using these approaches. Lee et al. now report a new type of DNA-based nanoparticle for siRNA delivery. These self-assembling nanoparticles are built from six different DNA oligonucleotides, resulting in a uniform population of tetrahedron-shaped particles where each of the six edges can accommodate one siRNA molecule. To increase the tumor-targeting capabilities, the authors conjugated folic acid onto the siRNAs. These triangular pyramids are designed to be large enough to minimize uptake by the kidneys but small enough to enter solid tumors through the leaky vasculature. Upon intravenous injection into a tumor-bearing mouse, fluorescently labeled tetrahedrons containing folic acid conjugated-siRNA were primarily localized to the tumor and the kidney. Serum half-life of nanoparticle-borne siRNA was increased significantly over naked siRNA. Systemic injection knocked down targeted gene expression in the tumor. Future studies will explore the potential to use these and other types of DNA-based nanoparticles to deliver other therapeutic agents. (Nat. Nanotechnol. 7, 389–393, 2012)