Nanoscale Spatial Engineering of Ligands Using DNA Origami for Precise Modulation of Membrane Receptor Signaling

ABSTRACT Dimerization or multimerization of surface membrane receptors is essential for transmitting extracellular recognition events across the plasma membrane, triggering intracellular signaling cascades, and regulating a wide range of cellular functions. Ligands typically act as inducers for these processes by binding to receptors, promoting their aggregation and subsequent dimerization or multimerization. The precise spatial arrangement of ligands is crucial for minimizing random collisions and non‐directed migration of receptors on the cell membrane, thereby enhancing signaling fidelity. DNA origami, a highly versatile self‐assembly technique, has emerged as a powerful tool for generating a wide variety of DNA nanostructures. Its exceptional programmability and spatial addressability enable fine‐tuned control over ligand spatial arrangement at the nanoscale, facilitating the precise modulation of surface membrane receptor signaling and enabling user‐defined biological investigations. In this review, we explore the methods used to engineer the spatial arrangement of ligands through DNA origami, highlighting its unique advantages in controlling ligand distance, valence, spatial configuration, and stoichiometry. We also present current applications of DNA origami for modulating membrane receptor signaling, while addressing the key challenges and future directions in achieving precise nanoscale spatial arrangements of ligands for biological and therapeutic purposes.