Engineered molybdenum disulfide nanosheets as scavengers against oxidative stress inhibit ferroptosis to alleviate acute kidney injury

Acute kidney injury (AKI) is a common clinical kidney dysfunction associated with high morbidity, elevated mortality, and poor prognosis. It results from redox imbalance caused by abnormal excess production of endogenous reactive oxygen species (ROS) at the renal tubules, which in turn initiates a series of pathological processes, such as cellular apoptosis, necrosis, and ferroptosis, eventually 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 strategies to scavenge excessive ROS and thereby inhibit ferroptosis represents a promising strategy for AKI management. Herein, 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, rescued cell viability by consuming various forms of cellular ROS and significantly facilitated 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 superior biological stability and therapeutic effects 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.