Programmable Assembly of Artificial Antigen-Presenting Cells with Framework Nucleic Acids.

T cell activation by natural antigen-presenting cells depends on nanoscale ligand organization that dynamically reorganizes upon receptor engagement. Mimicking this spatial precision and adaptive ligand reorganization in synthetic systems remains challenging. Here, we introduce a programmable assembly of framework nucleic acids (FNA) to construct artificial antigen-presenting cells (FNA-aAPCs) with adaptive nanoscale control over ligand organization. The FNA-aAPCs, assembled hierarchically from tetrahedral framework nucleic acid (tFNA) units, precisely regulate anti-CD3 (αCD3) ligand spacing, valency, and density, enabling adaptive ligand configurations that match receptor reorganization and thereby directing TCR clustering and activation. Shorter ligand spacing and higher valency synergistically enhance T cell activation, as indicated by marker upregulation and cytokine secretion. The FNA-aAPCs promote TCR clustering, drive T cell proliferation, and mitigate T cell exhaustion, demonstrating the potential of programmable and adaptive ligand configurations. These results establish FNAs as an adaptively programmable and biomimetic platform for engineering artificial immune interfaces.