Bilirubin-Modified Chondroitin Sulfate-Mediated Multifunctional Liposomes Ameliorate Acute Kidney Injury by Inducing Mitophagy and Regulating Macrophage Polarization
Ziqi Shen, Xiaohua Wang, Lu Li, Runkong Wang, Danni Hu, Ziyan Fan, Liyang Zhu, Ruixue Zhong, Mingquan Wu, Zhou Xu, Xi Cao
Abstract
Acute kidney injury (AKI) is a dynamic process associated with inflammation, oxidative stress, and lipid peroxidation, in which mitochondrial mitophagy and macrophage polarization play a critical role in the pathophysiology. Based on the expression of the CD44 receptor on renal tubular epithelial cells (RTECs) and activated M1 macrophages being abnormally increased, accompanied by up-regulation of reactive oxygen species (ROS) during AKI, the conjugates of bilirubin (BR), an endogenous antioxidant which has the property of anti-inflammation, and chondroitin sulfate (CS) with CD44-targeting property could be a promising therapeutic carrier. In this study, we develop a CD44-targeted/ROS-responsive CS-BR-mediated multifunctional liposome loading celastrol (CS-BR@CLT) for the targeted therapy of AKI. CS-BR@CLT is shown to selectively accumulate in AKI mouse kidneys via targeting of CD44 receptors. Treatment with CS-BR@CLT significantly ameliorates acute kidney injury caused by ischemia-reperfusion and protects renal function. Mechanistically, CS-BR@CLT inhibits apoptosis, protects mitochondria, promotes autophagy, regulates macrophage polarization, and alleviates interstitial inflammation. Overall, our study demonstrates that CS-BR@CLT could be a promising strategy to ameliorate acute kidney injury.