Our immune system is outfitted with a plethora of sensors to discriminate friend from foe. Precisely engaging these sensors is critical to the success of immune-interventions for vaccines (i.e. activation) and autoimmune therapies (i.e. dampening). Materials with tailor-made structure, valency, solubility, and release profiles, for example via mimicry of natural pathogens, represent an innovative approach for controlled immuno-modulation. Using DNA nanostructures as a programmable core buidling block, we explore how engineered combinations of signals can lead to synergistic immuno-modulatory properties.