A Spatially Controllable DNA Origami-Based T-Cell Cluster Engager for Precise Tumor Elimination

  • J Am Chem Soc. 2026 Jan 21;148(2):2758-2768. doi: 10.1021/jacs.5c19678.
Hua-Dong Li  1  2 ,  Wen-Jia Shi  1 ,  Jianjun Xu  3 ,  Chao-Qiang Li  4 ,  Yue Liu  1 ,  Tianhao Zou  3 ,  Ying-Fu Li  1 ,  Pei-Qiang Ma  1 ,  Bang-Ce Ye  1 ,  Bin-Cheng Yin  1  4
Affiliations
  • 1. Lab of Biosystem and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.
  • 2. Institute of Molecular Medicine and Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
  • 3. Liver Transplant Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
  • 4. School of Chemistry and Chemical Engineering, Shihezi University, Shihezi, Xinjiang 832000, China.
PMID: 41504034 DOI: 10.1021/jacs.5c19678
Abstract

T cell-engaging therapy represents a cutting-edge approach in immuno-oncology that harnesses the power of the immune system to combat Cancer. Despite its promise, challenges related to efficacy and safety limit its broader clinical application. Here we introduce SpTCE, a spatially controllable T-cell cluster engager based on DNA origami technology. SpTCE features an elegant two-layer architecture built on a DNA origami chassis. The inner functional layer is engineered to organize multiple, multivalent engaging antibodies and complementary hand-in-hand strands, which work together to enhance T-cell clustering and activation. The outer shielding layer integrates albumin binding domains with i-motif switches, which form a pH-responsive albumin coat and serve two functions: isolating the inner layer from healthy tissues and improving the structural stability of the DNA origami through an albumin coat. We validate acidic pH-triggered, specific T-cell cytotoxicity of SpTCE against tumor cells in vitro and observe the substantial intratumoral accumulation and improved physiological stability in vivo. As a proof of concept, we show that SpTCE effectively redirects T cells to eliminate tumors with high specificity and a more favorable off-tumor toxicity profile than a clinical-stage bispecific T cell engager. Collectively, these findings highlight the potential of SpTCE as a promising T-cell engager, offering precise control over T-cell activation while balancing efficacy and safety, and expanding the possibilities for advanced immuno-oncology treatments.

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