Geometry‐Programmable Living Immunomaterials for Spatial Control of Innate Immune Signaling

Spatial organization of immune ligands critically regulates cGAS-STING signaling by controling the nanoscale geometry that drives cooperative cGAS assembly and catalytic activity. Here we engineer geometry-programmable DNA origami that precisely encodes double-stranded DNA (dsDNA) valency and spacing to promote cooperative cGAS clustering and STING activation. Systematic architectural modulation identifies an optimal configuration within tested ranges, in which 60-bp dsDNA ligands arranged with ∼16.3 nm periodicity induce approximately twofold stronger STING signaling than free dsDNA counterparts. We further integrate these origamis with the probiotic Escherichia coli Nissle 1917 via transporter-mediated surface anchoring, forming a living immunomaterial interface for localized ligand presentation in colorectal tumors. In microsatellite-stable colorectal cancer models, this biohybrid system drives robust intratumoral STING activation, promotes T-cell-inflamed immune remodeling, and suppresses tumor growth by ∼83.5% relative to controls. This work establishes a geometry-programmable living immunomaterial translating nanoscale architectural design into spatially confined innate immune signaling.