Regulating the iron-ROS cycle via electronic structure-engineered nanoregulators for Parkinson's disease therapy

Iron-driven reactive oxygen species (ROS) amplification forms a self-sustaining pathological cycle in Parkinson's disease (PD), yet remains difficult to therapeutically interrupt due to the lack of strategies that coordinate metal homeostasis and redox regulation. Here, we report an electronic-structure-engineered nanoregulatory strategy that regulates the iron-ROS cycle rather than passively scavenging ROS. Nitrogen-doped, herbal-derived carbon dots (CD) were rationally constructed to establish a conjugated electronic framework, in which heteroatom-induced electron delocalization defined redox-active sites and governed the coupling between iron chelation and catalytic ROS regulation. This structure-electronic state-function relationship enabled programmable disruption of the iron-ROS feedback loop at its source. Functionally, the nanoregulators achieved low-density lipoprotein receptor-related protein 1 (LRP1)-mediated brain delivery, exhibited efficient central nervous system exposure, and underwent brain clearance via the cerebrospinal fluid pathway. At the cellular level, they restored mitochondrial function, suppressed ferroptosis-associated lipid peroxidation, and reprogramed stress-related pathways toward neuronal survival. Transcriptomic analysis further revealed coordinated regulation of redox, metabolic, and inflammatory networks. In Parkinsonian mice, this strategy reduced iron deposition, preserved dopaminergic neurons, and improved motor function. Integration with levodopa further enabled sustained, disease-modifying neuroprotection.