Spatially Defined DNA Origami Cell Engagers for T and Natural Killer Cell-Mediated Immune Modulation

Cell engagers have emerged as a promising approach for cancer immunotherapy, yet their efficacy is often limited by structural constraints in antibody valency and spatial configuration. Here, we present a DNA origami-based platform for the precise spatial organization of antibodies, enabling the construction of tailored multivalent cell engagers to enhance antitumor immunity. By modulating the composition, valency, and spatial arrangement of antibodies on a single DNA origami scaffold at the single-molecule level, we developed two types of cell engagers, T cell engagers and natural killer cell engagers, that effectively activate immune cells and improve tumor specificity. In vitro studies demonstrated that both engagers elicited specific and effective immune responses against epidermal growth factor receptor (EGFR)-expressing tumors. Furthermore, in vivo studies using murine solid tumor models validated the efficacy of both engagers in inhibiting tumor growth. This study demonstrates the potential of DNA origami as a versatile and programmable platform for engineering precision immunotherapies and highlights its utility for targeted tumor eradication.