Bioinspired DNA Framework‐Programmed Heteroligation for Affinity‐Enhanced Biodetection

Natural polyreactive antibodies achieve enhanced avidity through heterogeneous ligand binding. However, engineering synthetic heteroligation systems with precise control over recognition motif orientation and distance remains challenging. Here, a DNA framework-based strategy is presented to program heterotypic binding by spatially organizing bivalent aptamers targeting platelet-derived growth factor-BB (PDGF-BB). By systematically tuning the distance between heterotypic recognition motifs, programmable modulation of binding affinity is demonstrated. The resulting heteroligation exhibits rapid binding kinetics, high specificity, and ultrasensitive detection of PDGF-BB, with a limit of detection reaching 0.5 pM. This approach provides a versatile platform for designing multivalent interactions, with potential applications in disease diagnostics and immunotherapy for cancer, viral infections, and allergic disorders.