Mechanistic insights into the inhibition of α-synuclein aggregation by sugar-based nanoparticles

The pathological accumulation of α-synuclein (α-syn) into amyloid fibrils is a key hallmark of Parkinson's disease and related synucleinopathies. Inhibiting the early stages of α-syn aggregation remains a major therapeutic challenge. In this work, we report the fabrication and investigation of five sugar-based nanoparticles (NPs), including glucose, fructose, maltose, sucrose, and trehalose, and their ability to inhibit α-synuclein aggregation. Using a combination of biophysical strategies, comprising thioflavin-T fluorescence, dynamic light scattering, circular dichroism, and confocal microscopy, we illustrate that sugar NPs prevent β-sheet formation and the growth of α-syn fibrils in a concentration-dependent manner. Isothermal titration calorimetry revealed spontaneous, high-affinity interactions between α-syn and sugar NPs, suggesting direct binding to aggregation-prone regions. Importantly, cytotoxicity assays using SH-SY5Y neuroblastoma cells showed that NP-treated α-syn aggregates exhibited significantly reduced neurotoxicity. Collectively, these findings demonstrate that sugar-derived nanoparticles act as potent inhibitors of α-syn aggregation during the lag phase, thereby stabilizing non-toxic conformers. These results highlight the promise of sugar-based nanostructures as biocompatible and mechanistically active molecules for modulating synucleopathies associated with various neurodegenerative disorders.