Self-oriented ferritin nanocages mitigate iron overload-induced oxidative stress for acute kidney injury

Abstract

Iron overload-induced oxidative injury of renal tubular epithelial cells plays crucial roles in the pathogenesis of ischemia–reperfusion acute kidney injury (IR-AKI). Curcumin is a polyphenolic compound that can effectively scavenge free radicals, but its poor water solubility and renal distribution restrict its application. Although nanotechnology helps to improve this situation by enabling solubility and renal accumulation, the headstream of oxidative injury, iron overload, has not been reverted. Ferritin (Fer) is a well-known iron storage protein with a favorable particle size for renal filtration that can potently transport excess iron into its core to prevent further oxidative damage. In this regard, ferritin nanocages loaded with curcumin (FNC/Cur) were prepared. It is worth noting that ferritin nanocage-based proteins showed a significant self-orientation capability into injured kidneys at 4 h. After kidney aggregation, glomerular filtration and renal tubular reabsorption, FNC/Cur finally internalized by the target cells (renal tubular epithelial cells) under the mediation of transferrin receptor-1 (TfR1). Once internalized, FNC/Cur released curcumin to reduce excess reactive oxygen species (ROS) with the help of lysosomal acidic environment and protease-rich environment. At the same time, the dissembled FNC or their released heavy chain are able to bind lysosomal redox-active iron for a period of time, thereby temporarily protect against iron-mediated oxidation. As a result, FNC/Cur represents a potential kidney-targeted nanoplatform for synergistic treatment of IR-AKI.