Nanozyme-augmented clinical drug strategy for dopaminergic restoration and oxidative stress mitigation to rescue motor and cognitive deficits in Parkinson's disease.

Current treatments for Parkinson's disease (PD) fail to halt dopaminergic neurodegeneration and remain largely ineffective against cognitive impairment. Here, we developed IP@ALipo, a nanoplatform that co-delivers the clinical drug pramipexole (PPX) and PEGylated iron oxide nanozyme particles (PEG-IO) via Angiopep-2-modified liposomes capable of crossing the blood-brain barrier (BBB). In the PD mouse model, in vivo photometry showed that a single dose of IP@ALipo significantly enhanced dopaminergic signaling from the substantia nigra pars compacta (SNc) to the striatum (STr) via its PPX component. Facilitated by PEG-IO in IP@ALipo, repeated administration further suppressed cerebral ROS and promoted sustained dopaminergic recovery, resulting in improved motor function. Importantly, the PEG-IO component also preserved hippocampal neurons and restored synaptic architecture, yielding pronounced cognitive benefits. This study demonstrates a nanozyme-augmented strategy for clinical drugs that not only sustains nigrostriatal dopaminergic recovery but also provides cognitive improvements beyond conventional Parkinson's treatments, offering a comprehensive therapeutic approach.