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<p>Amyloid-β (Aβ) fibrillation is a key pathological event in Alzheimer’s disease (AD), promoting the development of nanomaterial-based inhibitors that can function in protein-rich biological media. PEGylated nanoparticles are attractive for such applications because poly(ethylene glycol)(PEG) coronas suppress nonspecific protein adsorption and enhance colloidal stability; however, how PEG content influences Aβ fibrillation remains insufficiently understood. Here, we report how the degree of PEGylation modulates the inhibitory activity of protein-based nanoparticles toward Aβ fibrillation. We selected lysozyme (LYZ) as a model protein and synthesized PEG–LYZ conjugates bearing 3–10 PEG chains per protein (<i>N</i><sub>PEG</sub>), followed by nanoparticle formation via a nanoemulsion method. PEG–LYZ conjugates with <i>N</i><sub>PEG</sub> ≥ 5 formed colloidally stable nanoparticles. Compared with the molecular forms, nanoparticulation increased the apparent surface hydrophobicity of PEG–LYZ and enhanced the suppression of Aβ<sub>42</sub> fibrillation. Among the series, the inhibitory activity of the PEG–LYZ(10) nanoparticles was the greatest, and the nanoparticles maintained their dispersibility after they interacted with Aβ<sub>42</sub>, as evidenced by ThT fluorescence assays together with TEM and DLS analyses. QCM measurements further indicated appreciable Aβ<sub>42</sub> binding but only minimal adsorption of model proteins, which is consistent with antifouling behavior. These findings highlight PEG content as a key design parameter governing nanoparticle formation, Aβ inhibition, and nonspecific protein adsorption in PEGylated protein nanoparticles.</p>

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PEGylated protein nanoparticles for the inhibition of Aβ fibrillation via Aβ binding with minimal nonspecific protein interactions

  • 期刊论文

  • 发表日期：

    2026年4月30日

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  • Tomonori Waku,
  • Takashi Yoshikawa,
  • Michiaki Okuda,
  • Hachiro Sugimoto,
  • Kazuya Matsuo,
  • Akio Kobori

摘要

Amyloid-β (Aβ) fibrillation is a key pathological event in Alzheimer’s disease (AD), promoting the development of nanomaterial-based inhibitors that can function in protein-rich biological media. PEGylated nanoparticles are attractive for such applications because poly(ethylene glycol)(PEG) coronas suppress nonspecific protein adsorption and enhance colloidal stability; however, how PEG content influences Aβ fibrillation remains insufficiently understood. Here, we report how the degree of PEGylation modulates the inhibitory activity of protein-based nanoparticles toward Aβ fibrillation. We selected lysozyme (LYZ) as a model protein and synthesized PEG–LYZ conjugates bearing 3–10 PEG chains per protein (NPEG), followed by nanoparticle formation via a nanoemulsion method. PEG–LYZ conjugates with NPEG ≥ 5 formed colloidally stable nanoparticles. Compared with the molecular forms, nanoparticulation increased the apparent surface hydrophobicity of PEG–LYZ and enhanced the suppression of Aβ42 fibrillation. Among the series, the inhibitory activity of the PEG–LYZ(10) nanoparticles was the greatest, and the nanoparticles maintained their dispersibility after they interacted with Aβ42, as evidenced by ThT fluorescence assays together with TEM and DLS analyses. QCM measurements further indicated appreciable Aβ42 binding but only minimal adsorption of model proteins, which is consistent with antifouling behavior. These findings highlight PEG content as a key design parameter governing nanoparticle formation, Aβ inhibition, and nonspecific protein adsorption in PEGylated protein nanoparticles.