Condensate-enhanced catalytic photo-oxygenation for early intervention in tau amyloidosis

Aberrant aggregation of tau protein is a hallmark of neurodegenerative disorders, including Alzheimer’s disease. Inhibiting tau aggregation is, therefore, a promising therapeutic strategy. While photocatalytic oxygenation of tau amyloid reduces its pathological properties, such as seeding activity, early intervention targeting pre-aggregated tau remains challenging due to difficulties in selective targeting. Here, we show that rose bengal and its analogs are preferentially concentrated in tau droplets formed via liquid-liquid phase separation. Structure-activity relationship analysis and machine learning-based ADMET predictions reveal key physicochemical properties, such as hydrophobicity, that promote photocatalyst enrichment in these droplets. Within droplets, photocatalysts efficiently and selectively induce photo-oxygenation of tau. This process alters droplet properties and prevents subsequent amyloid formation, which is otherwise accelerated in condensates. This work establishes a strategy for early intervention in amyloid formation and provides a framework for developing prophylactic therapies against tauopathies and related protein aggregation disorders.