Strategic physicochemical tuning: amphiphilic polymers as molecular regulators of amyloid aggregation and cytotoxicity

Abstract

Amyloidogenesis is a central pathological process in neurodegenerative disorders, yet general chemical principles that enable its predictive control are still insufficiently understood. Synthetic polymers offer a versatile and chemically tunable platform for modulating amyloid assembly; however, quantitative relationships linking polymer physicochemical properties to amyloidogenic pathways and biological outcomes remain poorly established. Here we present a systematic and quantitative framework that connects polymer composition to amyloid reactivity. By precisely tuning hydrophobicity, hydrophilicity, and net charge, and integrating polymer synthesis with computational, biochemical, and cellular analyses, we uncover clear structure-activity relationships governing interactions with amyloidogenic peptides and proteins, such as amyloid-β and α-synuclein. We show that balanced amphiphilic architectures, particularly hydrophobic-zwitterionic compositions, suppress fibrillization, redirect aggregation pathways, and reduce cellular membrane association, thereby attenuating cytotoxicity. In contrast, cationic-rich polymers promote aggregation via electrostatically driven mechanisms, while hydrophobic-dominant polymers exhibit minimal regulatory effects. Importantly, these composition-dependent behaviors are conserved across distinct amyloid systems, establishing a generalizable physicochemical framework in which the interplay between amphiphilicity and charge dictates amyloid reactivity and cellular responses. Overall, this work provides design principles for polymer-based chemical modulators and a broadly applicable strategy for controlling protein aggregation in neurodegenerative disease contexts.