Abstract

Hypoxic–ischemic encephalopathy (HIE) is a major cause of neurological injury in neonates, with pathological cascades such as neuroinflammation and ferroptosis driving disease progression. Current therapeutic strategies for HIE are largely limited to supportive care and therapeutic hypothermia, which fail to effectively target these mechanisms. To address this challenge, we developed a microglia-derived exosome–liposome hybrid membrane systems (HMS) (R+si@LPs-TK/TAT+Exo, abbreviated as Rs@LP-T/T-E) for the co-delivery of resveratrol (RES) and acyl-CoA synthetase long-chain family member 4 (ACSL4) siRNA. The nanosystem exhibited favorable stability, reactive oxygen species (ROS)-responsive drug release, and efficient blood–brain barrier (BBB) penetration, enabling targeted accumulation within ischemic brain regions. In experimental models, Rs@LP-T/T-E significantly attenuated neuroinflammation and ferroptosis, promoted microglial polarization toward the anti-inflammatory M2 microglial phenotype, and restored mitochondrial function, thereby reducing cerebral infarct volume and improving cerebral perfusion. In conclusion, this study presents an efficient, targeted, and biocompatible nanodelivery strategy that holds strong translational potential for HIE therapy.