Self-assembly of amyloid beta-protein (A beta) is closely related to the pathogenesis of Alzheimer's disease (AD). Many studies suggest that polymeric nanoparticles (NPs) can inhibit A beta fibrillogenesis depending on their electrostatic and hydrophobic properties, but the underlying molecular mechanism remains unknown. Herein, the inhibitory effect of NPs with equivalent content of hydrophobic groups but different surface negative charge densities on A beta fibrillogenesis is examined. Firstly, the polymeric NPs of similar sizes were synthesized by copolymerizing equal proportion of N-isopropylacrylamide and different proportion of N-t-butylacrylamide and acrylic acid. Then, the inhibitory effects of these NPs on A beta(42) fibrillization and the corresponding cytotoxicity were investigated using thioflavin T fluorescent assay, transmission electron microscopy, dynamic light scattering analysis, and cell viability assay. It was found that these NPs showed remarkable inhibitory capability against A beta(42) fibrillogenesis and alleviated its cytotoxicity. The inhibitory capability significantly depended on the capacity of the negative surface charges carried by NPs with an increase-decrease trend. The best inhibitory efficiency was obtained at an optimal surface negative charge density. Based on the findings, a mechanistic model wasproposed by considering the two interactions between A beta(42) and NPs, namely, hydrophobic binding and electrostatic repulsion. The model suggested that at an appropriate negative charge capacity, the two opposite forces could be well-balanced, and thus led to the stretching of A beta(42) molecules instead of the formation of a harmful beta-sheet structure. The polymeric NPs of well-designed surface of proper hydrophobicity and negative charge density could thus significantly slow down the A beta(42) fibrillation and/or result in an off-pathway aggregation with reduced cytotoxicity. (C) 2016 Elsevier B.V. All rights reserved.