Abstract
Amyloid fibrils and associated protein aggregates are key contributors to a range of neurodegenerative diseases. Recent studies suggest that nanoparticles with tailored surface chemistries can effectively bind to and disrupt these fibrils. Here, we investigate the role of nanoparticle surface charge in mediating interactions with amyloid fibrils and promoting their disintegration. We synthesized seven types of charged iron oxide nanoparticles (cationic, anionic, and ampholytic) in colloidal form with hydrodynamic diameters ranging from 15 to 40 nm. Interaction studies with mature lysozyme fibrils revealed that ampholytic nanoparticles exhibited the highest binding affinity among the tested surface types. This enhanced affinity is attributed to reduced nonspecific interactions and favorable electrostatic compatibility. Ampholytic nanoparticles disrupted mature amyloid fibrils approximately 2.5 times more effectively than other surface-charged nanoparticles, leading to smaller fibril fragments via mechanical agitation. We further show that agitation-induced mechanical force, along with piezocatalytically generated reactive oxygen species (ROS), contributes to fibril degradation. These findings highlight the critical role of ampholytic surface charge in promoting fibril disintegration and suggest that such nanoparticles could be leveraged in therapeutic strategies for neurodegenerative diseases involving amyloid aggregation.