Coating with flexible DNA network enhanced T-cell activation and tumor killing for adoptive cell therapy

Adoptive cell therapy (ACT) is an emerging powerful cancer immunotherapy, which includes a complex process of genetic modification, stimulation and expansion. During these in vitro or ex vivo manipulation, sensitive cells are inescapability subjected to harmful external stimuli. Although a variety of cytoprotection strategies have been developed, their application on ACT remains challenging. Herein, a DNA network is constructed on cell surface by rolling circle amplification (RCA), and T cell-targeted trivalent tetrahedral DNA nanostructure is used as a rigid scaffold to achieve high-efficient and selective coating for T cells. The cytoprotective DNA network on T-cell surface makes them aggregate over time to form cell clusters, which exhibit more resistance to external stimuli and enhanced activities in human peripheral blood mononuclear cells and liver cancer organoid killing model. Overall, this work provides a novel strategy for in vitro T cell-selective protection, which has a great potential for application in ACT.