Diabetic nephropathy (DN) is a frequent and severe microvascular complication associated with oxidative stress of diabetes mellitus. A novel astaxanthin-based natural antioxidant nanosystem, namely AST-GLU-LIP, with preferential renal uptake and bioavailability were prepared and applied for treatment of diabetic nephropathy in rats. Our results of kidney-targeted evaluation showed that glucose-PEG600-DSPE ligand modified AST liposomes could be specifically transported by overexpressed GLUT1 on the membrane of glomerular mesangial cells and achieved excellent kidney-targeted drug delivery. In addition, the results of pharmacodynamics and therapeutics in DN rats demonstrated that AST-GLU-LIP could improve the bioavailability and antioxidant capacity of AST to scavenge redundant ROS induced by oxidative stress. AST-GLU-LIP could also significantly improve the renal pathological morphology to protect the kidney as a therapeutic drug for diabetic nephropathy.