Ischemic stroke remains a critical global health challenge with limited therapeutic options targeting secondary neuroinflammation. Emerging evidence implicates neutrophil extracellular traps (NETs) as key mediators of blood-brain barrier (BBB) disruption and neuronal damage during ischemia-reperfusion injury. Capitalizing on this pathophysiology, we engineered a neutrophil-homing lipid nanoparticle (LNP) platform encapsulating brensocatib (AZD7986), an FDA-designated breakthrough therapy that inhibits dipeptidyl peptidase 1 (DPP1) to block activation of neutrophil serine proteases. The LNPs exploit intrinsic neutrophil chemotaxis to achieve BBB penetration and lesion-specific accumulation, enabling localized release of AZD7986 in ischemic brain tissue. In a murine middle cerebral artery occlusion (MCAO) model, targeted LNP delivery (T-AZD) significantly prolonged survival, reduced cerebral infarct volume by 45 %, and suppressed NET formation through inhibition of elastase and cathepsin G activity (p < 0.01 vs. non-targeted controls). Mechanistically, T-AZD attenuated reactive astrogliosis and decreased pro-inflammatory cytokine levels (IL-6, TNF-α) by >50 %, demonstrating dual anti-inflammatory and neuroprotective effects. This neutrophil-directed nanoplatform addresses critical limitations of systemic DPP1 inhibition through spatiotemporal control of drug release, while exhibiting enhanced biocompatibility in hematological and histological safety assessments. By integrating targeted neutrophil trafficking with precision protease inhibition, our strategy establishes a translatable paradigm for modulating neuroimmune responses in cerebrovascular diseases. STATEMENT OF SIGNIFICANCE: Ischemic stroke lacks effective therapies targeting neuroinflammation. We developed neutrophil-homing lipid nanoparticles (LNPs) delivering brensocatib (AZD7986), a DPP1 inhibitor, to suppress neutrophil extracellular traps (NETs) and neuroinflammation. In a murine stroke model, targeted LNPs reduced infarct volume by 45 %, inhibited NET formation, and lowered pro-inflammatory cytokines (>50 %), demonstrating neuroprotection and anti-inflammatory effects. This approach enables precise drug delivery to ischemic brain tissue, overcoming limitations of systemic therapy while maintaining safety. By combining neutrophil-directed targeting with protease inhibition, our strategy offers a translatable platform for modulating neuroimmune responses in cerebrovascular diseases.
mRNA Technology