ROS-responsive hierarchical targeting vehicle-free nanodrugs for three-pronged Parkinson’s disease therapy

Although nanodrugs have shown striking potential toward Parkinson's Disease (PD) therapy, lack of brain targeting and on-demand drug release, as well as low drug payload seriously impede various nanodrugs further applied in PD. Here, motivated via the fact that the smart self-targeting nanodrugs can enhance blood–brain barrier (BBB) penetration, brain-targeting efficency, and cellular delivery, we have constructed a reactive oxygen species (ROS)-responsive hierarchical targeting vehicle-free nanodrugs for spatiotemporally selective PD therapy. Such nanodrugs are constructed via self-assembly of rasagiline mesylate (RM) and dopamine (DA)-thioketal-DA dimer. The obtained nanodrugs with high drug payload, excellent physiological stability, and suitable diamter can specifically cross BBB and then internalize into endothelial and neuronal cells through DA receptor-mediated transcytosis. After that, nanodrugs can be disassembled under stimuli of the PD-endogenous ROS, thereby resulting in simultaneous spatiotemporal on-demand burst release of DA and RM. Moreover, our new findings show that DA and RM released from nanodrugs possess an outstanding three-pronged therapeutic effect on PD by inhibiting α-synuclein (α-syn) aggregation and neuroinflammation and enhancing DA neurons survival. In a word, we propose a central nervous system disease microenvironment-responsive vehicle-free hierarchical targeting therapeutic strategy for PD therapy.