Copper-containing ROS-scavenging nanozyme paradoxically drives α-synucleinopathy by amplifying nitrosative stress

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.