Natural Metal Polyphenol Nanozyme: Free Radical Scavenging and Antioxidation for the Treatment of Acute Kidney Injury

Acute kidney injury (AKI) is a severe renal dysfunction syndrome associated with high morbidity and mortality. Excessive production of reactive oxygen/nitrogen species (RONS) is involved in the development and progression of AKI. Therefore, scavenging endogenous RONS and reducing excessive oxidative stress is essential for restoring renal function after AKI. Although nanozyme-mediated antioxidant therapy has been proposed as an effective strategy to prevent AKI, low renal uptake and high organ toxicity hinder its potential for practical applications. To address this problem, we have designed a metal-phenolic nanozyme named RosA-Mn NPs, which possesses cascade antioxidant functionalities. The nanozyme has multienzymatic cascade capacity as well as broad spectrum of ROS and free radical scavenging activities. As expected, RosA-Mn NPs promote the recovery of mitochondrial function and reduce endoplasmic reticulum stress and secondary inflammation through effective ROS scavenging in vitro. Moreover, RosA-Mn NPs overcome the shortcomings of artificial enzymes that failed to rapidly accumulate in kidney tissues. The renal tubular targeting of RosA-Mn NPs could be exploited to mitigate the tubular damage, improve tubular functions, and eventually prevent the progression of AKI. Notably, RosA-Mn NPs also protect kidney from oxidation and inflammation in a cisplatin-induced AKI mouse model. RNA sequencing analysis demonstrated that autophagy, apoptosis, and antioxidation-related pathways were modulated by the treatment with RosA-Mn NPs. In summary, the multienzymatic activities and biocompatibility of RosA-Mn NPs show great potential in the treatment of AKI and other ROS-related diseases.