Modular Design of T Cell Nanoengagers for Tumor Immunotherapy via Genetically Engineered Lipid‐Tagged Antibody Fragments

作者：Helong Kang, Yuanke Li, Fude Sun, Fan Li, Mingsheng Zhu, Zheng Zhou, Jin Wu, Keyu Wang, Buayishamu Kutilike, Zhizhao Miao, Yanqin Xu, Ruming Liu, Dan Ding, Hongkai Zhang, Xinglu Huang, Jie Zhuang · 发表于：Advanced Materials · 年份：2025 · DOI：10.1002/adma.202503060 · 被引用次数：6 · 研究领域：Monoclonal and Polyclonal Antibodies Research、CAR-T cell therapy research、Immunotherapy and Immune Responses

Abstract T cell engagers, which bind tumor‐associated antigens and T cell specific molecules, represent a promising class of immunotherapies for enhancing targeted immune responses. Here, a “plug‐and‐display” platform is introduced for engineering T cell nanoengagers by anchoring antibody fragments into lipid‐based nanoparticles. This approach utilizes a genetically engineered lipoprotein fused with single‐chain variable fragments (scFv) and nanobodies, which spontaneously integrate into lipid bilayer of the nanoparticles, achieving a high surface density of at least 0.102 scFv nm −2 (≈3200 scFv per particle). Modular bi‐specific (Lipo‐BiTE) and tri‐specific (Lipo‐TriTE) immunoliposomes are designed to enhance anti‐tumor T cell immune responses. The Lipo‐BiTE, integrating anti‐CD3 and anti‐HER2 scFv at an optimized surface density of 1.28 × 10 −3 scFv nm −2 , exhibits enhanced CD8 + T cell‐mediated cytotoxicity in HER2‐positive tumor models by simultaneously engaging tumor cells and T cells. Incorporating anti‐PD‐L1 nanobodies to create Lipo‐TriTE further addresses T cell exhaustion. This modular platform provides a robust foundation for designing immune cell engagers, with broad applications in targeted immunotherapy.