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DNA nanostructures have shown great potential in biomedical fields. However, the immune responses, especially the activation of the cGAS‐STING signaling (A‐cGSs), induced by DNA nanostructures, remain incompletely understood. Here, the ability of various DNA nanostructures from double‐stranded DNA (dsDNA), single‐stranded tiles (SSTs) to DNA origami is investigated on A‐cGSs. Unlike natural dsDNA which triggers potent A‐cGSs, the structural interconnectivity of various DNA configurations can substantially reduce the occurrence of A‐cGSs, irrespective of their form, dimensions, and conformation. However, wireframe DNA nanostructures can activate the cGAS‐STING signaling, suggesting that decreasing A‐cGSs is dsDNA compactness‐dependent. Based on this, a reconfigurable DNA Origami Domino Array (DODA) is used to systematically interrogate how dsDNA influences the A‐cGSs and demonstrates that the length, number, and space of dsDNA array coordinately influence the activation level of cGAS‐STING signaling, realizing a regulation of innate immune response. The above data and findings enhance the understanding of how DNA nanostructures affect cellular innate immune responses and new insights into the modulation of innate immune responses by DNA nanomedicine. [ABSTRACT FROM AUTHOR]