This collection of research articles and reviews covers the latest work in the design, delivery, dynamic abilities, and immune stimulation of RNA nanoparticles which have driven the utilization of their immunomodulatory properties. The unknown immune properties of nucleic acid nanoparticles have been a major hurdle in their adaptation until the works herein began assessing their structure-activity relationships. This collection chronologically follows the path of investigating the recognition of design components to implementing them into nucleic acid nanostructures. RNA nanotechnology is an emerging platform for therapeutics with increasing clinical relevance as this approach becomes more widely used and approved for the treatment of various diseases. The latest research aims to take advantage of RNA’s modular nature for the design of nanostructures which can interact with their environments to communicate programmed messages with intracellular pathways. In doing so, nanoparticles can be used to elicit or elude responses by the immune system as desired in conjunction with their therapeutic applications.