Yumeng Lu

An urgent requirement in chimeric antigen receptor (CAR) immune cell therapy [e.g., CAR–natural killer (NK) cells] for solid tumors is to engineer the cells for precise tumor targeting. Meanwhile, medical microrobots can be navigated toward specific target sites using external magnetic fields. Here, by bridging these approaches, we turn CAR-NK cells into magnetic biohybrid microrobots (CAR-NK microrobots) that achieve controllable long-distance targeted navigation at therapeutic doses (∼10 ⁶ cells) in both murine and nonhuman primate animal models in vivo. CAR-NK microrobots are developed through genetic engineering with CAR structures and loading with magnetic nanoparticles for field-based navigation. Different magnetic field inputs reconfigure their swarms between vortex and ribbon modes, allowing dense aggregation for targeted navigation and further broad dispersion for large-area coverage. Using programmable magnetic fields, in vivo CAR-NK microrobot–based therapy is demonstrated for metastatic leptomeningeal carcinomatosis in brain’s cerebrospinal fluid space. After intrathecal injection, the microrobots are magnetically guided long distance through the spinal canal toward the brain in vortex mode and subsequently spread over the target site in ribbon mode, as visualized by real-time angiographic imaging in a nonhuman primate model, providing a proof-of-feasibility demonstration in a nonhuman primate anatomical setting.

Intrathecal delivery for central nervous system (CNS) therapy lacks spatiotemporal control due to spinal canal anatomical constraints, especially at human scale. We developed an adaptive magnetic nanorobotic platform enabling multimode swarm mobility for in vivo spinal canal navigation in mice and nonhuman primates. Programmable chain-like, vortex-like, and ribbon-like swarm were accomplished, and vortex swarm was indicated as optimal strategy for adaptive intrathecal navigation. Driven by a robotic arm–generated magnetic field, the vortex swarms indicate navigation within spinal canal over centimeter distances, which magnetically enhanced accumulation at CNS target sites and prolonged their in vivo retention, thereby substantially enhancing their therapeutic efficacy compared with conventional passive intravascular delivery, with minimal side effects. Tests in nonhuman primates indicate that the nanorobotic swarm migration is from the gap between the bundles of cauda equina and then the spin cord, revealing their morphological adaption at the cauda equina interface to circumvent anatomical constraints.