Copper-containing ROS-scavenging nanozyme paradoxically drives α-synucleinopathy by amplifying nitrosative stress
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Reactive oxygen and nitrogen species (RONS) are implicated in neurodegeneration, but their specific pathogenic roles remain unclear. Here, we developed a pair of iridium-based nanozymes with opposing functionalities to dissect these pathways. We show that a copper-tuned iridium nanozyme (Ir□Cu), despite being a superior ROS scavenger, paradoxically and dramatically exacerbated α-synuclein (αSyn) pathology in vivo . This pathology was causally linked to its ability to amplify RNS, as pharmacological inhibition of nitric oxide synthase (NOS) with L-NAME completely abrogated the pathology and reversed a human Parkinson’s disease (PD)-like transcriptomic signature. In contrast, a copper-free, broad-spectrum RONS-scavenging iridium (Ir) nanozyme demonstrated substantial therapeutic efficacy across diverse brain-first, body-first, and Alzheimer’s disease with Lewy body co-pathology models. Our findings uncover the importance of the RNS pathway in driving α-synucleinopathies and establish a critical design principle for nanomedicine, mandating caution in the use of redox-active copper for neuroprotective applications.
