Shear-Sensitive Clustering of Nanoparticles and their Protein Corona Composition Govern α-Synuclein Aggregation

Abstract

Nanoplastics and engineered nanoparticles interact in varying ways with amyloidogenic proteins, yet the mechanistic basis for the pathological effects caused by that interplay remains unclear. Here, we demonstrate how carboxylated -polystyrene nanoplastics (PsNPs) and -silica nanoparticles (SNPs) differentially modulate α-synuclein (αSyn) amyloid formation kinetics through variation in composition and binding of the protein corona, a surface layer of biological origin formed from plasma proteins. Using Taylor dispersion analysis in microfluidic capillaries under physiologically relevant flow conditions, we demonstrate that anionic PsNPs form shear-sensitive, αSyn-bridged clusters, which transition into stable flocs at sub-stoichiometric ratios via charge neutralization. SNPs, in contrast, maintain colloidal stability through dynamic binding equilibria. The composition of the hard corona, a tightly bound layer of protein at the NP surface with slow exchange kinetics, critically determined aggregation outcomes: PsNPs accelerated fibril formation through strong interfacial interactions, while SNPs inhibited nucleation but promoted fibril fragmentation. We identified the hard corona's slow exchange kinetics as the primary determinant of long-term aggregation, while the weakly bound “soft corona” mediated early interaction dynamics. These findings extend the current understanding of how NP surface chemistry influences corona composition and protein aggregation particularly in the context of environmentally relevant nanoplastics.