Targeting the Labile Iron Pool with Engineered DFO Nanosheets to Inhibit Ferroptosis for Parkinson's Disease Therapy

Abstract Ferroptosis in neurons is considered one of the key factors that induces Parkinson's disease (PD), which is caused by excessive iron accumulation in the intracellular labile iron pool (LIP). The iron ions released from the LIP lead to the aberrant generation of reactive oxygen species (ROS) to trigger ferroptosis and exacerbate PD progression. Herein, a pioneering design of multifunctional nanoregulator deferoxamine (DFO)‐integrated nanosheets (BDPR NSs) is presented that target the LIP to restrict ferroptosis and protect against PD. The BDPR NSs are constructed by incorporating a brain‐targeting peptide and DFO into polydopamine‐modified black phosphorus nanosheets. These BDPR NSs can sequester free iron ions, thereby ameliorating LIP overload and regulating iron metabolism. Furthermore, the BDPR NSs can decrease lipid peroxidation generation by mitigating ROS accumulation. More importantly, BDPR NSs can specifically accumulate in the mitochondria to suppress ROS generation and decrease mitochondrial iron accumulation. In vivo experiments demonstrated that the BDPR NSs highly efficiently mitigated dopaminergic neuronloss and its associated behavioral disorders by modulating the LIP and inhibiting ferroptosis. Thus, the BDPR‐based nanovectors holds promise as a potential avenue for advancing PD therapy.