Engineered Molybdenum Disulfide Nanosheets as Scavengers Against Oxidative Stress and Inhibit Ferroptosis to Alleviate Acute Kidney Injury

Abstract

Acute kidney injury (AKI) is a common clinical kidney dysfunction associated with high morbidity, elevated mortality, and poor prognosis. It is related with redox imbalance caused by abnormal excess production of endogenous reactive oxygen species (ROS) at the renal tubules, causing a series of pathological processes such as cellular apoptosis, necrosis, and ferroptosis, leading to structural and functional impairment of the kidney. Thereinto, ferroptosis induced by the lethal accumulation of lipid peroxidation is extensively involved in renal damage. Nanotechnology-mediated therapeutic strategy to scavenge excessive ROS and inhibit ferroptosis represent a promising strategy for AKI management. Here, we report two engineered ultrathin molybdenum disulfide (MoS2) nanosheets (NSs) modified with polyvinylpyrrolidone (PVP) and bovine serum albumin (BSA), respectively, with excellent biocompatibility and antioxidative defense capability for AKI treatment. The engineered NSs, with a readily variable valence state of molybdenum ions, were able to rescue cell viability by consuming various forms of cellular ROS and significantly facilitates glutathione peroxidase 4 (GPX4) expression to mitigate ferroptosis in renal tubular epithelial cells. In a glycerol-induced AKI mouse model, the PVP-MoS2 NSs were largely accumulated in the injured kidneys, where they provided robust antioxidative protection against ROS attack and suppressed the oxidative stress-induced inflammatory response, thereby maintaining normal kidney function. Of the two engineered NSs, PVP-MoS2 displayed far superior biological stability and therapeutic effect and could thus serve as a powerful antioxidant platform for use in the treatment of AKI and other ROS-associated diseases. This study underscores the potential of two-dimensional nanomaterials in precisely treating AKI and other ferroptosis-related diseases.