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

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, we introduce a “plug-and-display” platform 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 integrated into lipid bilayer of the nanoparticles, achieving a high surface density of at least 0.102 scFv/nm2 (approximately 3200 scFv per particle). We designed modular bi-specific (Lipo-BiTE) and tri-specific (Lipo-TriTE) immunoliposomes 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/nm2, exhibited 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 addressed T cell exhaustion. This modular platform provides a robust foundation for designing immune cell engagers, with broad applications in targeted immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE293206 | GEO | 2025/05/01

REPOSITORIES: GEO

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