Lipoic acid zwitterionic polymer engineered nanozymes ferried by neutrophil reprogramming ischemic microenvironment for stroke treatment

The accumulation of pathological reactive oxygen species (ROS) after reperfusion of ischemic stroke (IS) triggers the cascade of "oxidative stress-mitochondrial apoptosis-NLRP3 pyroptosis", which aggravates neuronal death and neuroinflammation. In view of the limitations of traditional single-target therapies that are difficult to simultaneously block the vicious cycle of multiple pathways, a neutrophil-ridden zwitterionic engineered nanozyme (PLSP@CeO₂) based on neutrophils was constructed. The system achieves efficient blood-brain barrier crossing through sialic acid/L-selectin-mediated targeted delivery, and executes a synergistic therapeutic mechanism: mimicking superoxide dismutase/catalase dual enzyme activity to scavenge ROS, simultaneously inhibiting mitochondrial apoptosis and NLRP3 inflammasome-mediated pyroptosis, and driving microglia to polarize to the M2 anti-inflammatory phenotype to remodel the microenvironment. In vitro and <i>in vivo</i> experiments have confirmed that the system significantly reduces the volume of cerebral infarction, reduces neuronal death, and promotes angiogenesis and neurological repair. This study not only addresses key limitations of traditional nanozyme single-target therapy, but also establishes a multi-mechanism synergistic treatment paradigm based on endogenous immune cells, providing a new strategy for neurodegenerative diseases.