Nucleic acids are programmable and biocompatible polymers that have beneficial uses in nanotechnology with broad applications in biosensing and therapeutics. In some cases, however, the development of the latter has been impeded by the unknown immunostimulatory properties of nucleic acid-based materials, as well as a lack of functional dynamicity due to stagnant structural design. Recent research advancements have explored these obstacles in tandem via the assembly of three-dimensional, planar, and fibrous cognate nucleic acid-based nanoparticles, called NANPs, for the conditional activation of embedded and otherwise quiescent functions. Furthermore, a library of the most representative NANPs was extensively analyzed in human peripheral blood mononuclear cells (PBMCs), and the links between the programmable architectural and physicochemical parameters of NANPs and their immunomodulatory properties have been established. This overview will cover the recent development of design principles that allow for fine-tuning of both the physicochemical and immunostimulatory properties of dynamic NANPs and discuss the potential impacts of these novel strategies.