DNA origami: Interrogating the nano-landscape of immune receptor activation

The immune response is orchestrated by elaborate protein interaction networks that interweave ligand-mediated receptor reorganization with signaling cascades. While the biochemical processes have been extensively investigated, delineating the biophysical principles governing immune receptor activation has remained challenging due to design limitations of traditional ligand display platforms. These constraints have been overcome by advances in DNA origami nanotechnology, enabling unprecedented control over ligand geometry on configurable scaffolds. It is now possible to systematically dissect the independent roles of ligand stoichiometry, spatial distribution, and rigidity in immune receptor activation, signaling, and cooperativity. In this review, we highlight pioneering efforts in manipulating the ligand presentation landscape to understand immune receptor triggering and to engineer functional immune responses.