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

Abstract

ABSTRACT 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.