Abstract
<title>Abstract</title> <p>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. 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 (OGD/R) 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-κB inhibition and PPARγ 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.</p>