Phytocarbon Nanodots Restore Glutathione Homeostasis via γ-Glutamylcysteine Synthetase against Ferroptosis-Driven Renal Fibrosis

Renal fibrosis remains a critical and refractory clinical condition, characterized by a dire lack of safe and effective pharmacological interventions. Its progression is propelled by dysregulated ferroptosis, an iron-dependent cell death pathway that drives pathological extracellular matrix deposition. To bridge this translational gap, we engineered a novel class of intrinsic nanotherapeutics through the atomic-level reengineering of Lycium barbarum polysaccharides (LBP) into phytocarbon nanodots (LBPCDs). This transformation transcends the inherent pharmacokinetic limitations of native LBP, yielding emergent therapeutic properties. The resulting LBPCDs exhibit a defect-rich sp 2/sp 3 hybrid framework with quantum confinement (~2.5 nm), which facilitates superior renal accumulation and electron-transfer dynamics. Their redox-active surface, dominated by hydroxyl groups, confers potent scavenging capacity against ROS (·OH, ·O 2 -) and lipid peroxides, effectively alleviating oxidative stress and epithelial-mesenchymal transition. Mechanistic studies indicate that LBPCDs modulate the ferroptosis defense pathway, potentially through interactions with the glutamate-cysteine ligase modifier subunit (GCLM), leading to enhanced γ-glutamylcysteine synthetase activity and restoration of glutathione homeostasis. This dual-action strategy concurrently inhibits lipid peroxidation and ferroptosis, reversing fibrotic pathology in cisplatin-induced fibrosis and diabetic nephropathy models with exceptional biosafety. Our work establishes an innovative "material‑is‑the‑drug" paradigm, synchronizing oxidative homeostasis restoration, ferroptosis interception, and EMT remodeling, thereby presenting a promising next-generation nanotherapeutic platform for fibrotic diseases.