Magnetic-acoustic Sequentially Actuated CAR T cell Microrobots for Precision Navigation and in-situ Antitumour Immunoactivation.

Despite its clinical success, chimeric antigen receptor T (CAR T) cell immunotherapy remains limited in solid tumours, owing to harsh physical barriers and immunosuppressive microenvironments. Here we describe a CAR T cell-based live microrobot (M-CAR T) created by decorating CAR T with immunomagnetic beads using click conjugation. M-CAR Ts are capable of magnetic-acoustic actuation for precision tumour targeting and in-situ activation of antitumour immune responses. Sequential actuation endows M-CAR Ts with magnetically actuated anti-flow and obstacle avoidance capabilities as well as tumour tissue penetration driven by acoustic propulsion, enabling efficient migration and accumulation in artificial tumour models. In animal models, sequentially actuated M-CAR Ts achieved long-distance targeting and accumulated at the peritumoural area under programmable magnetic guidance, and subsequently acoustic tweezers actuated M-CAR Ts to migrate into deep tumour tissues, resulting in a 6.6-fold increase in accumulated exogenous CD8 + CAR T cells compared with that with no actuation. Anti-CD3/CD28 immunomagnetic beads in-situ stimulate infiltrated CAR T proliferation and activation in situ, significantly enhancing their antitumour efficacy. Thus, our sequential actuation-guided cell microrobot combines the merits of autonomous targeting and penetration of intelligent robots with in-situ immunoactivation of T cells, and holds considerable promise for precision navigation of cancer immunotherapies. This article is protected by copyright. All rights reserved.