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

• DOI: 10.1002/adma.202503060
• Publication Date: 2025-04-22T04:32:05Z
• Authors: 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

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