Engineered Macrophage Microrobots Exert Precise Neuroprotection Against Ischemic Stroke by Regulating the Polarization of Inflammatory Microglia

ABSTRACT The blood brain barrier (BBB) is a formidable challenge in the treatment of ischemic stroke, substantially impeding the trans‐barrier delivery and the bioactivity of therapeutic agents. Macrophages demonstrate considerable potential as nanomedicine carriers due to their intrinsic capacity for exceptional biocompatibility with internalized nanoparticles and inflammation‐targeted tropism. Herein, a macrophage microrobot (CDA@RC) packaged curcumin (CUR)‐loaded nanoparticles (CDA NPs) was strategically fabricated, integrating the functions of BBB transmigration, active targeting of ischemic brain parenchyma, and controlled drug delivery. Owing to macrophages’ inherent inflammation tropism, ischemia‐localized CDA@RC was capable of recognizing the M1 phenotype microglia and directly delivering therapeutic payloads, so as to neutralize excessive reactive oxygen species (ROS) to ameliorate oxidative stress and reprogram the microglia from classical into M2 type, eventually reshaping the proinflammatory microenvironment to reinforce the survival of damaged neurons. Notably, CDA NPs could induce polarization of macrophage carrier to M2 phenotype, conferring intrinsic therapeutic properties and synergistically amplifying the neuroprotective effects of CDA@RC. The microrobots were able to penetrate BBB, selectively accumulate in ischemic tissues of stroke mice, and modulate M2 microglia polarization to reduce infarct volume and promote neurological recovery. Collectively, this study proposes a novel strategy based on living cells for stroke treatment.