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

Abstract

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.