Engineering hirudin encapsulation in pH-responsive antioxidant nanoparticles for therapeutic efficacy in ischemic stroke model mice

Abstract

This study introduces a novel pH-sensitive, hirudin-loaded antioxidant nanoparticle (HD@iNano^AOX) aimed at addressing the challenges of hirudin's short half-life and hemorrhagic transformation. HD@iNano^AOX was engineered to safeguard and prolong hirudin's bioactivity by encapsulating it within antioxidative nanoparticles, facilitating its gradual release in acidic environments. The efficacy of this approach was validated through both ex vivo and in vivo experiments. Ex vivo thrombolytic assays demonstrated that HD@iNano^AOX maintained effective clot lysis activity under acidic conditions. In vivo assessments revealed that HD@iNano^AOX significantly prolonged hirudin's half-life and reduced cerebral infarct volume in a mouse model of middle cerebral artery occlusion (MCAO). Furthermore, HD@iNano^AOX treatment mitigated cerebral oxidative stress, suppressed hemorrhagic transformation, and prevented blood-brain barrier (BBB) disruption. These findings suggest that the combined thrombolytic and antioxidative properties of HD@iNano^AOX offer a promising therapeutic approach for ischemic stroke. Nonetheless, further research is warranted to optimize the formulation and assess its safety and efficacy in clinical settings.