Engineering Ultrasmall Ferroptosis‐Targeting and Reactive Oxygen/Nitrogen Species‐Scavenging Nanozyme for Alleviating Acute Kidney Injury

Abstract Acute kidney injury (AKI) is a serious renal dysfunction syndromes, which predominantly correlates with the excess production of endogenous reactive oxygen/nitrogen species (RO/NSs), triggering a series of pathological processes including cellular apoptosis, renal fibrosis, and ferroptosis. Ferroptosis as an iron‐dependent nonapoptotic regulated cell death is extensively involved in renal damage. Herein, the authors report the engineering of ultrasmall KCa(H 2 O) 2 [Fe III (CN) 6 ]·H 2 O nanoparticles as multienzyme mimetics, termed as CaPB nanozymes, for effectively scavenging RO/NSs and further inhibiting ferroptosis for the treatment of AKI. CaPB nanoparticles can effectively mimic the activity of multienzymes including superoxide dismutase, catalase, peroxidase, and glutathione peroxidase. Furthermore, CaPB nanozymes serving as a robust ferroptosis inhibitor significantly increase the expression of ferroptosis regulator glutathione peroxidase 4 in vitro. Furthermore, the renal accumulation of CaPB nanozymes effectively protects the kidney from oxidative injury and alleviated ferroptosis after intravenous administration. Additionally, the abnormal expression of inflammatory factors is further inhibited by CaPB nanozymes. The results demonstrate that the engineered ultrasmall CaPB nanozyme as a multienzyme mimetic features high potential for RO/NSs scavenging and treating AKI via inhibiting ferroptosis, which promises the clinical translation on the treatment of AKI and other RO/NSs‐related renal diseases.