Metal-organic macrocycles as molecular modulators of amyloid-β aggregation and cytotoxicity.

Metal-organic macrocycles provide a versatile platform for integrating multiple chemical functions within a single, well-defined architecture, yet their potential for regulating pathological protein aggregation remains largely unexplored. Here we report rationally designed metal-organic macrocycles that combine piano-stool ruthenium or iridium complexes with a photoactivatable bis(difluoroboron)-1,2-bis((1H-pyrrol-2-yl)methylene)hydrazine (BOPHY)-based ligand to enable dual-mode modulation of amyloid-β (Aβ) aggregation associated with Alzheimer's disease. These macrocycles directly engage Aβ species through surface interactions and, upon light activation, induce oxidative modifications via singlet oxygen, collectively altering aggregation behavior and aggregate morphologies. As a result, they suppress the formation of toxic Aβ assemblies and attenuate Aβ-induced cytotoxicity. Overall, this work establishes metal-organic macrocycles as effective modulators of amyloidogenesis and provides a potential strategy for controlling complex protein aggregation processes in neurodegenerative diseases.