Engineering Receptor-Mediated Cell-Surface Mobility with Phage-Inspired DNA Tetrapods

Viruses have long inspired the development of multiligand display systems that engage cell surface receptors through strong multivalent interactions. However, considerably less attention has been devoted to recapitulating the early stages of infection, during which weak, reversible interactions promote receptor-mediated mobility across cell membranes. Bacteriophages provide a striking example of this behavior, using transient receptor interactions to move across bacterial surfaces in search of favorable binding sites. Inspired by this mechanism, we developed DNA tetrapods targeting bacterial receptors exploited by phages during adsorption and demonstrate that phage-like lateral mobility on living bacterial cells can be achieved by tuning ligand affinity, valency, and spacer length. Furthermore, this platform can be extended to mammalian systems, where the tetrapod architecture similarly governs lateral motion and cell association, enabling selective cancer-cell recognition and improved antisense oligonucleotide uptake. Together, these findings demonstrate receptor-mediated mobility as a promising design principle for enhancing cellular targeting and cargo delivery.