ROS‐Responsive Micellar Delivery of Bergapten for Coordinated Attenuation of Oxidative Stress and Neuroinflammation in Neonatal Hypoxic‐Ischemic Brain Damage

Neonatal hypoxic-ischemic brain damage (HIBD) represents a leading contributor to neonatal death and persistent neurological impairments, yet effective therapeutic options beyond hypothermia remain limited. Excessive reactive oxygen species (ROS) production and Toll-like receptor (TLR)-mediated neuroinflammation contribute to neuronal loss during hypoxic-ischemic injury. Here, a ROS-responsive antioxidant nanomicellar system (BGT@NPEP) based on an NPEP-PEG-PPG (NPEP) platform is reported for targeted delivery of the anti-inflammatory coumarin bergapten (BGT) to ischemic neonatal brain tissue. The nanomicelles incorporate ROS-cleavable boronate ester-linked nordihydroguaiaretic acid, conferring intrinsic antioxidant activity and stimulus-responsive drug release, while a neutral, size-controlled shell facilitates accumulation in the ischemic hemisphere. The therapeutic efficacy of BGT@NPEP was systematically evaluated in vitro using oxygen-glucose deprivation models and in vivo in neonatal HIBD models. Mechanistic investigations indicate that BGT@NPEP significantly reduced oxidative stress, enhanced glutathione peroxidase 1 (GPX1) activity, suppressed TLR-driven inflammatory signaling, and modulated microglial polarization by inhibiting the M1 phenotype and promoting M2 phenotype transition. These effects collectively attenuated neuronal injury, reduced infarct volume, and improved neurological outcomes. Overall, this study demonstrates a dual-action, ROS-responsive nanotherapeutic strategy that integrates redox regulation with targeted anti-inflammatory delivery, providing a promising minimally invasive approach for neuroprotection in neonatal HIBD.