Adaptive Antioxidant Nanomedicines Inhibit Ferroptosis in Renal Tubular Epithelial Cells to Alleviate Diabetic Kidney Disease

Abstract Diabetic kidney disease (DKD) imposes a heavy medical burden worldwide due to the lack of effective treatment. High levels of mtROS and mitochondrial damage in the renal tubules are the initiating and core factors driving the progression of DKD. However, the effectiveness of current antioxidant drugs is greatly limited, mainly due to the difficulty of simultaneously breaching the glomerular barrier and targeting tubular mitochondria, as well as their limited ability to sustain treatment of chronic DKD. Here, this study reports a Se embedded adaptive antioxidant nanodrug (AAN) with negative surface charge and high mitochondrial targeting that can pass through the renal tubules and be highly enriched in the affected renal tubular mitochondria in DKD. AAN can eliminate mtROS to release soluble Se, which is then converted into the key bioactive enzymes ‐GPX4, effectively inhibiting ferroptosis and protecting mitochondria by exerting adaptive antioxidant effects. In the DKD mouse model, AAN treatment can effectively restore renal function, and the therapeutic effect at a dose of 10 mg kg ⁻¹ every 4 days is significantly better than Metformin administered at a dose of 200 mg kg ⁻¹ per day. In conclusion, this study provides a promising strategy to enhance the effects of antioxidant therapy to break the pathological barriers in DKD treatment.