Bioreducible Cu2O Cluster-Glutathione Nanohybrids with Multienzyme-Mimetic ROS Scavenging for Cisplatin-Induced Acute Kidney Injury

Cisplatin (Cis)-induced nephrotoxicity remains a major clinical challenge, largely driven by reactive oxygen species (ROS)-mediated oxidative stress leading to acute kidney injury (AKI). Because effective therapies for AKI remain limited, antioxidants capable of scavenging ROS and selectively accumulating in injured kidney tissue are highly desirable. Artificial nanocatalysts have emerged as promising antioxidant therapeutics owing to their advantages over natural enzymes. Here, we developed bioreducible nanohybrids (GCuNPs) composed of copper(I) oxide (Cu 2 O) nanocatalysts stabilized by glutathione (GSH), synthesized via the reductive reaction of copper ions in the presence of ascorbic acid and GSH. GCuNPs exhibited enhanced broad-spectrum ROS-scavenging capacity and multi-enzyme-like activities in vitro . Following systemic administration in a Cis-induced AKI mouse model, GCuNPs preferentially accumulated in injured kidneys through an impaired glomerular filtration barrier and loosening of proximal tubular tight junctions. Immunofluorescence analysis revealed that GCuNPs significantly reduced the expression of KIM-1, a proximal tubular injury marker, while preserving HO-1 expression, indicating attenuation of tubular damage and preservation of endogenous antioxidant defense. Furthermore, GCuNP treatment significantly reduced serum creatinine and blood urea nitrogen levels, improved survival, and showed no noticeable toxicity. These findings highlight GCuNPs as a promising therapeutic strategy for mitigating Cis-induced nephrotoxicity and potentially other oxidative stress-associated kidney disorders. • Bioreducible GCuNPs consisting of ultrasmall Cu 2 O as the nanocatalyst and GSH as the robust stabilizer are fabricated. • GCuNPs provided remarkable cellular protection by scavenging ROS and exhibiting enhanced multi-enzyme-like activity. • GCuNPs markedly reduced KIM-1 expression and preserved HO-1 levels in kidney tissues, confirming attenuation of tubular injury and preservation of endogenous antioxidant defense. • GCuNPs significantly reduced creatinine and blood urea nitrogen levels, resulting in increased survival rates in AKI mice without noticeable toxicity.