In biology, function rarely depends on a single binding event. Whether it's cell signaling, immune recognition, or adhesion, most processes rely on a critical density of interactions that occur simultaneously and in close proximity. This multivalency ensures robustness, specificity, and tunability, features that single-molecule targeting approaches often fail to replicate. As a result, there is growing interest in engineering multivalent systems that can mimic or exploit these natural interaction patterns at biointerfaces. DNA-based nanomaterials, with their precise programmability and structural control, have emerged as powerful tools in this space. They enable the spatial organization of ligands at nanometer resolution, not only enhancing binding avidity but also allowing for the design of geometry-dependent and context-sensitive targeting strategies. This capability marks a conceptual shift from traditional multivalent binding toward what we define here as multivalent engineering: the deliberate spatial programming of ligand arrangements to control biological outcomes based on receptor organization, density, and local context. This review discusses the fundamental principles of multivalency at biointerfaces, highlights recent advances in DNA-enabled design strategies, and explores how this emerging framework of multivalent engineering is driving new applications in diagnostics, therapeutics, and synthetic biology. We also outline the major challenges that must be addressed to realize the full potential of these systems in complex in vivo environments.
Li et al. (Fri,) studied this question.