Therapeutic-scale CAR-NK microrobots with programmable swarm navigation for targeted solid tumor therapy

Abstract

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.