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.