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.