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.

尽管嵌合抗原受体T（chimeric antigen receptor T，CAR T）细胞免疫疗法已取得临床成功，但由于实体瘤存在严苛的物理屏障与免疫抑制微环境，其应用仍存在局限。本研究报道了一种基于CAR T细胞的活体微机器人（M-CAR T）：通过点击共轭（click conjugation）技术将免疫磁珠修饰于CAR T细胞表面构建而成。该M-CAR T细胞机器人可实现磁声驱动，能够精准靶向肿瘤并原位激活抗肿瘤免疫应答。时序驱动赋予M-CAR T机器人磁驱动抗流体流动与避障能力，同时借助声学推进实现肿瘤组织穿透，使其可在人工肿瘤模型中高效迁移并富集。在动物模型中，经时序驱动的M-CAR T机器人可在可编程磁引导下实现远距离靶向，并富集于肿瘤周围区域；随后通过声学镊子驱动其迁移至深部肿瘤组织，与未驱动组相比，外源CD8+ CAR T细胞的富集量提升了6.6倍。包被抗CD3/CD28的免疫磁珠可原位刺激浸润的CAR T细胞增殖与活化，显著提升其抗肿瘤功效。综上，本研究开发的时序驱动式细胞微机器人融合了智能机器人自主靶向与穿透的优势，以及T细胞原位免疫激活的特性，在癌症免疫疗法的精准导航领域展现出巨大应用潜力。