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

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.