Iterative‐Designed Multifunctional Carbon Dots Nanodrug for Celastrol Loading, Targeting Delivery, and Combination Therapy of Kidney Stones

ABSTRACT Kidney stones (KS) are a kind of common urological disease with high prevalence and recurrence rates, which is closely linked to oxidative stress in the renal microenvironment and ferroptosis of renal tubular epithelial cells. Clinical used citric acid drugs can only reduce stone formation while along with the concerns about their effectiveness and side effects. Therefore, developing effective drugs for KS has great clinical significance. Celastrol (Cel) is a potential therapeutic drug for KS. However, the narrow therapeutic window (LD50 of ≈3 mg kg −1 in mice) and poor targeting greatly limited its application. Through iterative optimization based on molecular docking and structure–activity relationship evaluation, this study designed “drug‐excipient integration” cerium‐doping glutathione carbon dots (Ce‐CDs) for Cel targeting delivery. The Ce‐CDs@Cel nanodrug showed obvious kidney accumulation and even KS targeting with good biosafety. Importantly, such system met three goals in a single stroke: erosion of stones directly, ferroptosis inhibition by up‐regulating the expression of the Slc7a11/GPX4 pathway, and remodeling renal microenvironment by reducing the expression levels of stone‐related molecules and reactive oxygen species. These synergistic effects significantly reduced the deposition of calcium oxalate crystals. Overall, the multi‐functional Ce‐CDs@Cel provide a pharmaceutical design strategy and new insights into the treatment of KS.