A Chimeric Conjugate of Antibody and Programmable DNA Nanoassembly Smartly Activates T Cells for Precise Cancer Cell Targeting

Abstract Synthetically directing T‐cells against tumors emerges as a promising strategy in immunotherapy, while it remains challenging to smartly engage T cells with tunable immune response. Herein, we report an intelligent molecular platform to engineer T‐cell recognition for selective activation to potently kill cancer cells. To this end, we fabricated a hybrid conjugate that uses a click‐type DNA–protein conjugation to equip the T cell‐engaging antibody with two distinct programmable DNA nanoassemblies. By integrating multiple aptameric antigen‐recognitions within a dynamic DNA circuit, we achieved combinatorial recognition of triple‐antigens on cancer cells for selective T‐cell activation after high‐order logic operation. Moreover, by coupling a DNA nanostructure, we precisely defined the valence of the antigen‐binding aptamers to tune avidity, realizing effective tumor elimination in vitro and in vivo. Together, we present a versatile and programmable strategy for synthetic immunotherapy.