DNA-Edited Ligand Positioning on Red Blood Cells to Enable Optimized T Cell Activation for Adoptive Immunotherapy.

: Artificial antigen presenting cells (APCs) with surface-anchored T cell activating ligands hold great potential in adoptive immunotherapy. However, it remains challenging to precisely control the ligand positioning on those platforms via conventional bioconjugation chemistry. Here, utilizing DNA-assisted bottom-up self-assembly, we are able to precisely control both lateral and vertical distribution of T cell activation ligands on red blood cells (RBCs). It is found that the clustered lateral positioning of peptide-major histocompatibility complex (pMHC) on RBCs with a short vertical distance to the cell membrane would be favorable for more effective T cell activation, likely owing to their better mimic of natural APCs. Such optimized RBC-based artificial APCs can stimulate T cell proliferation in vivo and effectively inhibit tumor growth via adoptive immunotherapy. DNA technology is thus a unique tool to precisely engineer the cell membrane interface and tune cell-cell interactions, promising for a wide range of applications including immunotherapy.