Nanoconjugation of chalcone derivatives and carbon nitride dots for the inhibition of tau aggregation.

Tau aggregation is a pathological hallmark of Alzheimer's disease, yet small-molecule inhibitors targeting this process often face limitations in solubility, selectivity, and bioavailability. In this study, we engineered a library of hybrid nanostructures by covalently conjugating eleven structurally diverse chalcone derivatives to carbon nitride dots (CNDs), aiming to enhance their physicochemical stability and therapeutic efficacy. The resulting CND-chalcone conjugates exhibited favorable aqueous dispersibility and minimal cytotoxicity in HEK293 and HeLa cells. In vitro aggregation assays revealed that the conjugates modulated tau fibrillization in a structure-dependent manner, with several hybrids, particularly those containing hydroxyl or selectively positioned methoxy groups, showing strong inhibitory effects. Thioflavin-T fluorescence assays confirmed that the most active conjugates disrupted both nucleation and elongation phases of fibril formation. Notably, one hybrid (CNDs-S6) outperformed its free chalcone counterpart, suggesting synergistic interactions between the nanoparticle platform and ligand. These findings highlight the potential of CND-chalcone architectures as multifunctional nanoinhibitors and offer a rational approach to designing aggregation-targeting nanotherapeutics for neurodegenerative disease intervention.