Passively-targeted Mitochondrial Tungsten-based Nanodots For Acute Kidney Injury

Background:Acute kidney injury（AKI）can lead to kidney dysfunction,resulting in substantial excess mortality.The emergence of AKI in clinical patients also brings great challenges to clinical rational drug use.Therefore,effective drugs for the prevention and treatment of AKI are urgently needed.The burst of reactive oxygen species（ROS）plays a key role in the pathological progression of AKI.And mitochondria are the main source of ROS in AKI,therefore mitochondria-targeted antioxidant therapy is very promising in the AKI treatment.This paper aims to construct ultra-small-sized tungsten-based nanodots（TWNDs）with strong ROS scavenging ability and evaluate their therapeutic effects in AKI,and further reveal the mitochondrial protective mechanism of TWNDs on AKI.Methods:（1）TWNDs were synthesized based on redox reactions and characterized by transmission electron microscopy,X-ray photoelectron spectroscopy,infrared spectroscopy,ultraviolet-visible spectroscopy,and CT imaging.（2）Hemolysis/cisplatin-induced ICR mouse AKI model was constructed based on glycerol/cisplatin,AKI model of HK-2 cell was induced based on H₂0₂,and inflammation model of Raw264.7 cell was induced based on LPS.（3）The therapeutic effect of TWNDs was evaluated by body weight monitoring,biomarkers detection of renal function,HE staining,DHE staining and in vivo oxidation level detection;（4）The biodistribution of TWNDs,mitochondrial protection and anti-inflammatory effects were studied by CT imaging,tissue TEM imaging,immunohistochemistry,Western blotting,TUNEL staining,Annexin V-FITC apoptosis detection,and immunofluorescence.Results:（1）Ultra-small-sized TWNDs not only had a strong ability to eliminate multiple ROS,but also had CT imaging capabilities.（2）TWNDs showed great therapeutic effect and biocompatibility for both hemolysis-induced and cisplatin-induced AKI,effectively reduced markers of renal dysfunction,alleviated renal oxidative stress and improved cell damage in the renal tissue area.（3）TWNDs passively targeted mitochondria in renal tubular epithelial cells,protected mitochondria from ROS damage,inhibited mitophagy,and reduced renal tubular cell apoptosis.（4）TWNDs had anti-inflammatory effects and reduced the infiltration of macrophages.Conclusions:TWNDs have shown promising therapeutic effects in AKI by passively targeting mitochondria,scavenging ROS,reducing tubular apoptosis and inflammatory cell infiltration.