ROS‐Responsive Hybrid Nanoparticles Enable Dual‐Target Neurovascular Repair via Blood–Brain Barrier‐on‐Chip Validation

Blood-brain barrier leakage and neuronal damage are interconnected pathological features of neurovascular diseases. However, existing therapeutic strategies often fail to address both components simultaneously. Here, a reactive oxygen species-responsive exosome-liposome hybrid nanoparticle is designed, which is capable of co-delivering siBACH1 and siGSDMD for dual-target gene therapy, aiming to concurrently mitigate neuronal oxidative stress and BBB pyroptosis. A major hurdle in neurotherapeutic development is the limited predictive accuracy of conventional in vitro BBB models, which often contributes to the translational gap between preclinical studies and clinical applications. To address this, a microfluidic blood-brain barrier-on-chip platform incorporating endothelial cells, astrocytes, and neurons, which dynamically recapitulates key pathological hallmarks of MPTP-induced neurovascular diseases, are developed. Both the blood-brain barrier-on-chip platform and in vivo studies demonstrate the efficacy of the hybrid nanoparticles in synergistically restoring blood-brain barrier integrity and neuronal function. By integrating a predictive blood-brain barrier-on-chip with advanced nanotherapeutics, this work provides a dual-target gene therapy strategy for synergistic neurovascular repair and proposes a new paradigm for precision intervention in neurovascular diseases.