Biomimetic Mineralized SOD Enzyme In Metal-organic Framework For Treatment Of Acute Kidney Injury

Acute kidney injury（AKI）,also known as acute kidney failure,is often accompanied by dramatic decline in urine output and renal function,leading to increased accumulation of metabolic waste products in the body.In clinical,apart from supportive treatment and renal replacement therapy,there appears to be no specific drugs to ameliorate AKI.Chemotherapy is one of the important causes of AKI.When a large number of chemotherapeutic drugs are metabolized from the kidneys,it triggers increased production of reactive oxygen species leading to the key clinical manifestation of nephrotoxicity.Some small molecule antioxidants,such as n-acetylcysteine（NAC）,have shown success in the alleviation of contrast-induced AKI.However,their poor bioavailability and specificity limit its application in the treatment of AKI.Excessive accumulation of ROS is known as a crucial pathogenentic factor that can contribute to AKI.Therefore,the effective elimination of ROS is considered to be a key strategy to protect renal function.Balance between ROS production and removal is regulated and controlled by enzymes involved in redox under normal and healthy physiological conditions.Superoxide dismutase（SOD）is the first enzyme found to defense against oxygen free radicals.It could catalyze the conversion of superoxide into hydrogen peroxide and water resulting in scavenging ROS.However,SOD has relatively short circulation half-life and does not easily pass through cell membrane,which limits its application in clinical.Therefore,there is an urgent need for a vector to improve its stability and cellular uptake.Metal organic frameworks（MOFs）are a new type of well-regulated inorganic crystalline materials.Compared with traditional nanomaterials,it possesses unique properties such as highly ordered pore structure,massive surface area and excellent physical and chemical properties.Zeolitic imidazolate frameworks-8（ZIF-8）is one of the most representative MOFs materials.It is a dodecahedron structure formed by the coordination of zinc ions and nitrogen atoms in 2-methylimidazole.In addition to the advantages of MOFs,ZIF-8 has been reported to possess advanced drug delivery property and favorable biocompatibility,which has been widely used in drug or gene delivery.In our previous studies,we found that ZIF-8 can be used as an effective carrier to delivery RNase A into cytosol to improve the efficacy of cancer treatment.Therefore,it is expected that ZIF-8 can successfully deliver SOD into cytosol and regulate the levels of ROS in the treatment of AKI.Herein,we successfully synthesized SOD@ZIF-8 nanoparticles by biomimetic mineralization.In vitro studies,it was found that SOD@ZIF-8 nanoparticles were taken up by cells by confocal laser scanning microscopy（CLSM）and had good antioxidant capacity.In a AKI mouse model induced by cisplatin,SOD@ZIF-8 nanoparticles could effectively accumulate in the kidney and showed an excellent therapeutic effect on kidney injury.These results illustrate that SOD@ZIF-8 nanoparticles can be used as a novel therapeutic approach for the treatment of AKI.