Programmed interactions of nucleic acids—including DNA and RNA—orchestrate genetic expression and downstream cellular processes at every level. The structures of nucleic acids rely on their sequences, which include traditional Watson-Crick base pairing as well as non-canonical interactions and which make bottom-up structural design predictable and feasible. By utilizing these biopolymers as materials for the design and assembly of nucleic acid nanoparticles (NANPs), defined scaffolds can be constructed to carry out specific interactions with other nucleic acids, immune receptors, and pathways. The design of NANPs offers the advantage of modularity over traditional therapeutic approaches, as the targeting features can be tailored without alteration of the overall pharmacokinetic profile. Here, the immunostimulatory design parameters of therapeutic NANPs are explored as well as the conditional activation of those therapeutic moieties, which work via the RNA interference pathway for post-transcriptional gene knockdown. Overall, the further development of dynamic NANPs aims to treat disease with greater individualized specificity and to induce strategic immune responses towards the development of personalized medicine.