Liposomes are widely used as synthetic analogues of cell membranes and for drug delivery. Lipid-binding DNA nanostructures can modify the shape, porosity and reactivity of liposomes, mediated by cholesterol modifications. DNA nanostructures can also be designed to switch conformations by DNA strand displacement. However, the optimal conditions to facilitate stable, high-yield DNA–lipid binding while allowing controlled switching by strand displacement are not known. Here, we characterized the effect of cholesterol arrangement, DNA structure, buffer and lipid composition on DNA–lipid binding and strand displacement. We observed that binding was inhibited below pH 4, and above 200 mM NaCl or 40 mM MgCl2, was independent of lipid type, and increased with membrane cholesterol content. For simple motifs, binding yield was slightly higher for double-stranded DNA than single-stranded DNA. For larger DNA origami tiles, four to eight cholesterol modifications were optimal, while edge positions and longer spacers increased yield of lipid binding. Strand displacement achieved controlled removal of DNA tiles from membranes, but was inhibited by overhang domains, which are used to prevent cholesterol aggregation. These findings provide design guidelines for integrating strand displacement switching with lipid-binding DNA nanostructures. This paves the way for achieving dynamic control of membrane morphology, enabling broader applications in nanomedicine and biophysics.

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Receptor dimerization geometry plays a significant role in signal transduction induced by growth factors and cytokines. A chemical strategy capable of controlling dimerization geometry provides a means for studying receptor activation mechanisms and designing novel agonists transducing fine-tuned receptor signaling. However, a generalized approach that can be applied to given receptors is still limited. In the present study, we propose a strategy using CiD agonists (circular DNA aptamer-based agonists), where circularized DNA is used as a rigid scaffold to present two receptor-binding aptamers from the duplex linker domain in a fixed distance and orientation. We targeted Met, a receptor for hepatocyte growth factor (HGF), and designed Met-binding CiD agonists with variable linker length. The designed CiD agonists demonstrated a distinctive periodic change in the receptor activation potential dependent on their linker length. This strategy represents a useful approach for the rational design of partial agonists that transduce fine-tuned receptor signaling and exert moderate biological activity.