Baicalin-loaded MOF-818 nanozyme for ischemic stroke treatment via ROS scavenging and neuroinflammation suppression

Abstract Ischemic stroke (IS) reperfusion induces neuronal damage through excessive reactive oxygen species (ROS) and neuroinflammation. Baicalin (Bai) shows antioxidant and anti-inflammatory effects but suffers from poor solubility and bioavailability. Metal-organic framework (MOF)-818, a zirconium-based framework with superoxide dismutase- and catalase-mimicking activity, efficiently scavenges ROS but lacks pharmacological versatility. Combining Bai with MOF-818 may offer multitarget neuroprotection in IS. To investigate the therapeutic efficacy and mechanisms of Bai-loaded MOF-818 (Bai@MOF-818) in IS. In vitro oxygen-glucose deprivation/reperfusion models using PC-12 cells and BV-2 microglia were employed to assess ROS scavenging, mitochondrial protection, apoptosis, and microglial polarization. In vivo , Bai@MOF-818 was stereotactically delivered into the ischemic core of rats subjected to transient middle cerebral artery occlusion. Neurological function, infarct volume, oxidative stress, apoptosis, and microglial polarization were evaluated. Bai@MOF-818 markedly scavenged ROS, restored mitochondrial membrane potential, and promoted M1-to-M2 microglial polarization via NF- κ B inhibition and PPAR γ activation. This led to reduced TNF- α /IL-6 and increased IL-10/Arg-1, alleviating neuroinflammation. Furthermore, Bai@MOF-818 inhibited neuronal apoptosis by suppressing Bax and cleaved caspase-3 while elevating the Bcl-2/Bax ratio. Histological analyses revealed preserved tissue integrity, enhanced neuronal survival, reduced infarct size and edema, and improved motor and sensory recovery. Bai@MOF-818 exerts synergistic antioxidant and anti-inflammatory actions, attenuates neuronal apoptosis, and enhances neurological recovery, representing a promising multitarget therapeutic for cerebral ischemia-reperfusion injury.