Bilirubin-Modified\nChondroitin Sulfate-Mediated Multifunctional\nLiposomes Ameliorate Acute Kidney Injury by Inducing Mitophagy and\nRegulating Macrophage Polarization

Acute kidney injury (AKI) is a dynamic process associated\nwith\ninflammation, oxidative stress, and lipid peroxidation, in which mitochondrial\nmitophagy and macrophage polarization play a critical role in the\npathophysiology. Based on the expression of the CD44 receptor on renal\ntubular epithelial cells (RTECs) and activated M1 macrophages being\nabnormally increased, accompanied by up-regulation of reactive oxygen\nspecies (ROS) during AKI, the conjugates of bilirubin (BR), an endogenous\nantioxidant which has the property of anti-inflammation, and chondroitin\nsulfate (CS) with CD44-targeting property could be a promising therapeutic\ncarrier. In this study, we develop a CD44-targeted/ROS-responsive\nCS-BR-mediated multifunctional liposome loading celastrol (CS-BR@CLT)\nfor the targeted therapy of AKI. CS-BR@CLT is shown to selectively\naccumulate in AKI mouse kidneys via targeting of CD44 receptors. Treatment\nwith CS-BR@CLT significantly ameliorates acute kidney injury caused\nby ischemia-reperfusion and protects renal function. Mechanistically,\nCS-BR@CLT inhibits apoptosis, protects mitochondria, promotes autophagy,\nregulates macrophage polarization, and alleviates interstitial inflammation.\nOverall, our study demonstrates that CS-BR@CLT could be a promising\nstrategy to ameliorate acute kidney injury.