In Vivo Generation and Manipulation of CAR‐T‐mimicking Cells via Magnetic Bispecific Nano‐antibody for Solid Tumor Therapy

Abstract The therapeutic efficacy of chimeric antigen receptor (CAR)‐T cell therapy in combating solid tumors remains constrained, primarily due to inadequate tumor infiltration and the immunosuppressive tumor microenvironment. Herein, we present a simple yet effective strategy for generating activated CAR‐T‐mimicking cells and enabling their magnetically guided migration into tumor tissues, thereby enabling a more potent and precise treatment of solid tumors. By functionalizing magnetic nanoparticles with anti‐CD3 antibodies (aCD3) and anti‐PDL1 antibodies (aPDL1), we have developed a magnetic bispecific nano‐antibody (M‐BiNanoAb), which effectively engages circulating T cells following intravenous administration and reprograms them into CAR‐T‐mimicking effector cells. Within this design, the aPDL1 and aCD3 moieties emulate the antigen‐recognition domain and signaling domain of traditional CAR structures, respectively. Remarkably, the strategic application of an external magnetic field enables the precise navigation of these bioengineered T cells toward solid tumor regions, thereby facilitating the eradication of PDL1‐overexpressing cancer cells. In preclinical models of solid tumors, this magnetically guided strategy for generating and manipulating CAR‐T‐mimicking cells demonstrated extraordinary antitumor activity, underscoring its transformative potential in advancing CAR‐T‐based therapies against solid malignancies.