Neutrophil-targeted nanoparticles delivering sivelestat alleviate cerebral ischemia-reperfusion injury by suppressing NETosis.

As a leading cause of disability and mortality, ischemic stroke (IS) constitutes 80-90% of all stroke cases, underscoring the need for effective therapies. The pathogenesis of IS critically involves neutrophil extracellular traps (NETs), with neutrophil elastase (NE) serving as a core enzymatic driver of NETosis and a prime therapeutic target. Herein, we report a neutrophil-targeted nanotherapeutic strategy designed to exploit the pharmacological action of the NE inhibitor Sivelestat (SIV). Our engineered nanoparticles (T-SIV) feature a formyl peptide receptor (FPR)-specific ligand for neutrophil targeting and reactive oxygen species (ROS)-responsive thioketal linkages for site-specific drug release. Evaluation in MCAO mice and OGD/R-injured PC12 cells confirmed the efficacy of T-SIV, which conferred multimodal neuroprotection by reducing cerebral infarct volume, alleviating edema, and restoring neurological function. The therapeutic mechanism entails the suppression of NE-dependent NETosis coupled with a shift in microglial polarization toward the anti-inflammatory M2 phenotype, resulting in dual modulation of neuroinflammation. This study thus introduces a neutrophil-hitchhiking nanoplatform that synergistically disrupts the NE-NETs axis and reprograms the inflammatory microenvironment, presenting a transformative approach for the treatment of ischemic stroke.