Hydrophilicity-Driven Modulation of Amyloid-β(1–40) Fibrillation by Engineered Nanomaterials

作者：Xuecheng Yang, Xiaoyu Zhang, Ge Yu, Yubin Ma, Xin Li, Yiyang Guo, Shuping Wang, Dan Ge, Changying Xue, Kun Jin, Bingbing Sun · 发表于：ACS Applied Materials & Interfaces · 年份：2025 · DOI：10.1021/acsami.5c12708 · 被引用次数：3 · 研究领域：Alzheimer's disease research and treatments、Computational Drug Discovery Methods、Nanocluster Synthesis and Applications

Amyloid-β (Aβ) fibrillation is a spontaneous, thermodynamic process governed by nucleation and elongation. While many studies have explored the ability of engineered nanomaterials (ENMs) to modulate Aβ fibrillation, such as inhibitors, promoters, and dual-modulators, the key physicochemical property of ENMs that determines this behavior remains unclear. In this study, we developed a comprehensive library of ENMs with well-controlled physicochemical properties, including surface charges, morphologies, and hydrophilicity, to systematically investigate their effects on Aβ40 fibrillation. We identified hydrophilicity as the primary determinant of ENM-mediated modulation, rather than surface charge or morphology. Thioflavin T (ThT) kinetics assays indicated that hydrophilic ENMs exhibited bidirectional modulation, both promoting and inhibiting fibrillation depending on concentration. This bidirectional effect results from a competition between accelerated nucleation and decelerated elongation. While hydrophobic ENMs exhibited only unidirectional inhibition from the initial nucleation phase, two-dimensional-NMR (2D-NMR) mechanism studies indicated that this difference resulted from specific interactions with Aβ40 residues. Hydrophilic ENMs targeted hydrophilic residues involved in elongation, including Arginine R5, Glycine G9, G25, G33, G37, and G38, Lysine K28, and Alanine A30, while hydrophobic ENMs bound to hydrophobic residues critical for nucleation, such as I31. These finding...