Structure‐Activity‐Based Electrode‐Fibril Interaction and Selective Electrochemical Disassembly of Fibrils via ROS‐Mediated Structural Collapse

The pathological aggregation of misfolded proteins into β-sheet-rich amyloid fibrils underlies a broad spectrum of debilitating diseases, yet strategies capable of effectively reversing these supramolecular assemblies remain an open challenge. Here, we demonstrate that a selective electrode-fibril interaction could be achieved by quantifying the ratio of solvent-exposed hydrophobic to polar residues. The interaction between insulin fibrils and graphite electrodes, compared to platinum, facilitates localization and selective degradation of β-sheet-rich amyloid fibrils under DC and pulsed-DC stimulation. Importantly, the higher ratio of solvent-exposed oxidation-prone amino acids assists the reactive oxygen species (ROS)-mediated catalytic oxidation and the selective degradation of insulin fibrils over lysozyme fibrils. Electrochemical stimulation not only disassembles fibrils but also reduces toxicity and restores insulin's biological activity. Overall, our findings highlight the critical roles of electrode-fibril interaction, surface-exposed oxidation-prone amino acids, and proximity-driven catalytic oxidation in dismantling fibrils, providing a foundation for amyloid-targeting electrotherapeutics.