KLVFF‐Guided Molecular Scissors: a Trojan Horse Strategy for Precision Photodynamic Dissolution of Aβ Aggregates

Abstract Alzheimer's disease (AD) is pathologically linked to the aggregation of amyloid‐ β (A β ) peptides into neurotoxic fibrils. Despite advancements in Alzheimer's therapeutics, current strategies fail to simultaneously target amyloid‐ β aggregation and oxidative stress, particularly with spatiotemporal precision. To address the limitations of conventional therapies, this study develops a photo‐responsive nanomaterial, conjugated polymer nanodots functionalized with chlorin e6 (Ce6) and KLVFF peptides (CNPs‐Ce6 50 ‐K 0.5 ), for targeted inhibition of A β 1‐42 fibrillization. The nanomaterial is synthesized via nanoprecipitation, integrating Ce6 for reactive oxygen species (ROS) generation and KLVFF for A β ‐specific recognition. Systematic characterization confirms its structural stability, tunable ROS production, and high biocompatibility. Fluorescence microscopy, TEM, and CD spectroscopy demonstrate that CNPs‐Ce6 50 ‐K 0.5 synergistically inhibits A β 1‐42 aggregation through dual mechanisms: 1) KLVFF‐mediated high‐affinity binding to A β monomers, preventing nucleation; 2) Ce6‐generated ROS under light irradiation, destabilizing β ‐sheet structures. This work establishes CNPs‐Ce6 50 ‐K 0.5 as a multifunctional platform for precise A β modulation, offering a promising strategy for AD therapeutics with spatiotemporal controllability and minimal off‐target effects.