Neutrophil-like cell membrane-coated metal-organic frameworks for siRNA delivery targeting NOX4 to alleviate oxidative stress in acute ischemic injury

Although reperfusion is the most effective treatment for acute ischemic stroke, it often results in serious secondary ischemia/reperfusion (I/R) injury due to oxidative stress. This oxidative stress primarily results from the overproduction of reactive oxygen species (ROS) during reperfusion which, in turn, is largely induced by high expression of NADPH oxidase 4 (NOX4). Inhibiting NOX4 gene expression has therefore been proposed as a direct approach to reduce ROS production and promote angiogenesis. Recognizing both the potential of siRNA-based therapies for selective gene silencing and the critical role of neutrophil-endothelial interactions during I/R injury, here we present a unique therapeutic approach where neutrophil-like cell membrane coated porous metal-organic framework nanoparticles are loaded with siNOX4 (M-MOF-siNOX4) and designed to target damaged brain microvascular tissue. These then mitigate oxidative stress by suppressing NOX4 expression. Using an in vitro oxygen-glucose deprivation/re-oxygenation model, we demonstrate that M-MOF-siNOX4 nanoparticles specifically bind to activated endothelial cells, effectively reducing NOX4 expression, decreasing both ROS production and cell apoptosis, and restoring cell viability. Use of an in vivo mouse model of middle cerebral artery occlusion further confirmed M-MOF-siNOX4 nanoparticles to substantially alleviate brain damage and protect neurological function following ischemic stroke. Taken together, our study presents an innovative and effective siRNA-based strategy for reducing oxidative stress in ischemic stroke therapy. STATEMENT OF SIGNIFICANCE: Ischemia/reperfusion (I/R) injury, a major complication of acute ischemic stroke, is primarily driven by oxidative stress due to the excessive production of reactive oxygen species (ROS). Current treatments targeting oxidative stress and cell death often lack specificity, leading to off-target effects. This study introduces an innovative nanoparticle-based therapy using neutrophil-like cell membrane-coated metal-organic frameworks (MOFs) to deliver siNOX4, an siRNA targeting NOX4, a key ROS-producing enzyme. This approach enhances targeted delivery, reduces ROS production and cell death, and significantly improves neurological recovery in stroke models. By overcoming the limitations of existing therapies, this strategy holds strong potential for revolutionizing ischemic stroke treatment and addressing other disorders related to oxidative stress.