Copper-Containing ROS-Scavenging Nanozyme Paradoxically Drives Alpha-Synucleinopathy by Amplifying Nitrosative Stress
Li, S.; Mao, Y.; Wang, N.; Zhang, J.; Zhi, X.; Chen, Y.; Si, J.; Yang, Q.; Kumbhar, R.; Joeng, D.; Song, J.-Y.; Yang, X.; Kang, B. G.; Khandekar, A.; Park, J.; Gao, Y.; Yu, S.; Chen, R.; Zhang, S.; Han, J.; Dawson, V. L.; Liu, P.; Han, S.; Dawson, T.; He, W.; Mao, X.
Show 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{square}Cu), despite being a superior ROS scavenger, paradoxically and dramatically exacerbated -synuclein (Syn) 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 Parkinsons 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 Alzheimers disease with Lewy body co-pathology models. Our findings uncover the importance of the RNS pathway in driving -synucleinopathies and establish a critical design principle for nanomedicine, mandating caution in the use of redox-active copper for neuroprotective applications.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.