Self‐Assembled Trispecific T Cell Nanoengagers for Enhanced Cancer Immunotherapy

Abstract Trispecific T cell engagers (Tri‐TCEs) hold significant promise for tumor immunotherapy but face challenges from complex manufacturing and low production yields. Herein, a nanobody‐based trispecific T cell nanoengagers platform, termed Tri‐Nb@FNP is introduced, which leverages the modular and programmable assembly of nanobodies on ferritin nanoparticles (FNP) via SpyTag/SpyCatcher bioconjugation technology. These nanoengagers are designed to target EGFR‐positive triple‐negative breast cancer (TNBC) or HER2 positive breast cancer, alongside CD3 and CD28 on T cells, thereby facilitating precise immune synapse formation. This synergistic interaction robustly enhances T cell activation, proliferation and cytotoxicity, promotes cytotoxic CD8 ⁺ T cell infiltration into the tumor microenvironment, and achieves significant tumor suppression both in vitro and in vivo. Tri‐Nb@FNP is thus established as a novel class of Tri‐TCEs, offering a simple and efficient self‐assembly platform to integrate multispecific targeting molecules for advancing cancer immunotherapy.