Targeted Cell–Cell Interactions by DNA Nanoscaffold‐Templated Multivalent Bispecific Aptamers

Abstract Cell–cell interactions are essential for multicellular organisms, playing important roles in their development, function, and immunity. Herein a bottom‐up strategy to construct self‐assembled DNA nanostructures is reported, consisting of multivalent, bispecific, cell‐targeting aptamers to specifically induce cell–cell interactions. Various DNA nanoscaffolds are rationally designed to assemble aptamers with different valencies and flexibilities, and their cellular binding capabilities are tested. Multivalent aptamers, assembled on more rigid scaffolds, display higher binding activities. Further, multivalent bispecific aptamer fusion molecules are constructed based on this configuration, and successfully link two types of cells. Using cell‐targeting aptamers, the presented strategy eliminates the need to chemically modify cell surfaces and offers excellent cell specificity, binding efficiency, and stability. This proof‐of‐concept study establishes that multivalent bispecific aptamers linked on DNA‐nanoscaffolds can mediate cellular engagement, which could lead to their use in directing or guiding cell–cell interactions in many biological events.