Targeting Gasdermin D‐Mediated Pyroptosis With Microglial Membrane‐Coated Single‐Atom Nanozymes for Immune Microenvironment Reprogramming and Early Brain Injury Mitigation After Subarachnoid Hemorrhage

ABSTRACT Integrated analysis of single‐cell RNA sequencing (scRNA‐seq) data from clinical subarachnoid hemorrhage (SAH) patient samples and public databases reveals that SAH‐induced early brain injury is driven by excessive reactive oxygen species (ROS) production, microglial inflammatory activation, and Gasdermin D (GSDMD)‐mediated pyroptosis. It remains a devastating disorder with few effective therapeutic interventions. Current interventions fail to target the interconnected “ROS‐inflammation‐pyroptosis” cascade, while pyroptosis inhibitors (such as NU6300) suffer from poor bioavailability and blood‐brain barrier (BBB) penetration. Herein, we developed a microglial membrane (MM)‐coated drug delivery system (V/SAN‐NU@M), consisting of vanadium (V)‐based single‐atom nanozymes (SANs) encapsulated with NU6300. Leveraging the homing ability of M1‐like microglia, V/SAN‐NU@M efficiently crossed the BBB and accumulated at neuroinflammatory foci post‐SAH. Functionally, V/SAN‐NU@M exhibited robust antioxidant activity to eliminate excessive ROS, and sustained NU6300 release to inhibit the NLRP3‐GSDMD axis‐mediated pyroptosis. Comprehensive in vitro, in vivo evaluations, and scRNA‐seq confirmed that V/SAN‐NU@M reprogrammed the “ROS‐GSDMD‐microglia‐neuron” axis: it suppressed microglia shift from cytotoxic M1/Slco2b1 + toward reparative M2/F13a1 + phenotypes, enabled neurons to regain Nrg1‐Erbb4 signaling, and extinguished the pyroptotic–apoptotic cascade, disrupted the neuroinflammation‐oxidative damage cycle, and reduced neuronal loss. In SAH mice, V/SAN‐NU@M significantly improved survival rate, restored neurological function, and enhanced spatial memory.