Targeted Degradation of STING by a Neutrophil Membrane‐Coated Nanoplatform Suppresses Microglial Pyroptosis After Subarachnoid Hemorrhage

ABSTRACT Subarachnoid hemorrhage (SAH) is a life‐threatening cerebrovascular disease in which neuroinflammation and neuronal death critically contribute to poor outcomes. Here, we identify aberrant STING activation as a key driver of microglial pyroptosis and post‐SAH injury. Transcriptomic and biochemical analyses support a close association between STING signaling and microglial pyroptosis, with MAPK signaling acting as a functionally relevant downstream pathway. Based on this mechanistic insight, we engineered MG1 peptide‐functionalized, neutrophil membrane‐coated STING‐PROTAC nanoparticles (MG1@NM‐Px) to enable blood‐brain barrier penetration, microglia‐targeted delivery, and efficient STING degradation in vivo. This catalytic degradation suppressed the inflammasome‐related activation and GSDME‐associated pyroptotic signaling, reduced pro‐inflammatory cytokine secretion, and prevented neuronal apoptosis. Histopathological examination showed preserved Nissl body integrity, while behavioral testing revealed significant improvements in neurological function. Collectively, this engineered neutrophil membrane‐coated STING‐PROTAC nanoplatform effectively degrades STING, inhibits microglial pyroptosis, and provides robust neuroprotection in SAH. This work establishes a novel biomimetic nanomedicine strategy for SAH therapy and opens new avenues for treating neuroinflammation‐related disorders.