Neutrophil-targeting nanoparticles mitigate ischemic stroke injury by preventing neutrophil infiltration and NETosis

In the pathogenesis of ischemic stroke, neutrophil-driven inflammation and the formation of neutrophil extracellular traps (NETs) are key drivers of reperfusion injury. Interventions aimed at neutrophil infiltration and NET formation (NETosis) thus offer promise for alleviating ischemic damage, yet effective therapeutic options remain limited. To address this, we have developed neutrophil-targeted nanoparticles (PA@DBSA NPs), utilizing denatured bovine serum albumin (DBSA) as a carrier for the co-delivery of piceatannol (PIC) and all-trans retinoic acid (ATRA). PA@DBSA NPs selectively bind to activated neutrophils by targeting the highly expressed Fcγ receptor III (FcγRIII) on their surface, promoting efficient receptor-mediated endocytosis. Upon cellular uptake, PIC potently inhibits neutrophil adhesion and tissue infiltration, while ATRA suppresses NETosis. In a rat model of ischemic stroke, DBSA-based nanoparticles demonstrate improved brain-targeting capability via neutrophil-mediated hitchhiking. Treatment with PA@DBSA NPs significantly reduces neutrophil infiltration and NETosis, leading to attenuated neuroinflammation and robust neuroprotection. These effects are reflected in a marked reduction in cerebral infarct volume, from 37.3% to 12.3%. Our findings demonstrate that PA@DBSA NPs represent a promising nanotherapeutic strategy to address neutrophil-mediated reperfusion injury in ischemic stroke.