Renal-retentive PEGylated carbon dot nanozymes with SOD- and GPx-like activities suppress ferroptosis-associated fibrotic remodeling in obstructive kidney injury

Tubular epithelial cell (TEC) ferroptosis contributes to obstructive renal injury and fibrotic remodeling. Carbon dot nanozymes are promising antioxidant platforms, but their therapeutic application in chronic fibrotic kidney disease is hindered by rapid renal clearance and insufficient multifunctional antioxidant performance. Here, we engineer PEG600-modified carbon dot nanozymes (CDs-PEG) with complementary superoxide dismutase (SOD)- and glutathione peroxidase (GPx)-like activities and Fe 2+ -chelating capacity. Ex vivo organ imaging demonstrates a slower decay of renal-associated fluorescence for CDs-PEG, supporting their potential for sustained treatment of chronic kidney injury. In HK2 cells, CDs-PEG more effectively reduce reactive oxygen species, labile Fe 2+ , and lipid peroxidation, and partially preserve GPX4 and SLC7A11 expression under ferroptotic stress. In a unilateral ureteral obstruction mouse model, CDs-PEG also reduce renal tubular injury, 4-HNE accumulation, and collagen deposition more effectively than unmodified CDs. Mechanistically, CDs-PEG reduce ferroptosis-associated transforming growth factor-β1 (TGF-β1) release from TECs and attenuate TGF-β1-dependent macrophage-to-myofibroblast transition (MMT)-like remodeling. This study identifies CDs-PEG as a novel renal-retentive antioxidant nanozyme platform for sustained ferroptosis-targeted intervention and reveals a tubular ferroptosis–TGF-β1–macrophage pathway in MMT-like remodeling and obstructive renal fibrotic progression.