Celastrol-Loaded Targeted Antioxidative Nanozyme for Improving Lipid Metabolism and the Renal Microenvironment in Diabetic Nephropathy

Oxidative stress and abnormal lipid metabolism in podocytes and renal tubules are closely associated with the progression of diabetic nephropathy (DN). Conventional therapeutic agents for DN exhibit limited clinical efficacy due to inherent drawbacks such as poor target selectivity, short half-life, and unfavorable physicochemical properties. Therefore, the development of a safe and efficient targeted therapeutic strategy for DN has become urgently necessary. In this study, we constructed a targeted and reactive oxygen species (ROS)-responsive celastrol-loaded nanoplatform (termed meso-tetrakis(4-carboxyphenyl) porphyrin (TCPP)-Fe³⁺-Ce³⁺@Se-Se@Cyclo@Cel (TM-SeCC)), leveraging the antioxidant stress and lipolysis properties of celastrol (Cel) and the precise delivery capabilities of the nanoplatform to effectively inhibit DN progression. In vitro, TM-SeCC exhibited satisfactory antioxidant stress performance in a H₂O₂-induced podocyte inflammation model, significantly reducing intracellular ROS levels. Additionally, it exerted notable inhibitory effects on differentiated 3T3-L1 preadipocytes and demonstrated favorable hemolytic properties. In the DN mice model, TM-SeCC manifested good biosafety, enabled precise targeting of renal tissues, and prolonged retention in the kidneys. Mechanistically, the TM-SeCC nanozyme significantly reduced urinary protein levels in DN mice by improving lipid metabolism and repairing podocyte damage, thereby effectively reversing disease progression. Collectively, the TM-SeCC nanoplatform provides a promising strategy for safe and efficient DN treatment by integrating targeted delivery and redox-responsive drug release, offering insights into the translational application of nanomedicine for metabolic kidney diseases.