Aggregation of amyloid beta-protein (A beta) is a major pathological hallmark of Alzheimer's disease. Curcumin has been recognized as an inhibitor of A beta aggregation, but its low water solubility and bioavailability limits its clinical applications. In this work, we conjugated curcumin to hyaluronic acid and drastically improved its solubility and stability. We found that the conjugates self-assembled into nanosized hydrogels that inhibited A beta fibrillogenesis and mitigated the amyloid cytotoxicity more efficiently than free curcumin. More importantly, we found that there was an optimal curcumin substitution degree, at which the hydrogel exhibited the strongest inhibitory effect. Based on these findings, a mechanistic model was proposed. It suggested that besides the inhibitory effect of the conjugated curcumin, HA provided three synergistic functions. The first is that curcumin encapsulation into nanogels protected cells from the toxicity of free curcumin. The second was an isolation effect of the hydrogel network, which hindered the interactions between A beta molecules. The third was the counteraction of the hydrophobic binding between A beta and the conjugated curcumin against the electrostatic repulsion between the like charged A beta and HA. The two opposite forces could stretch the conformation of A beta monomers, slowing down the aggregation and/or leading to off-pathway aggregations. This work offered new insights into the development of more potent nanoparticles for inhibiting A beta fibrillogenesis and cytotoxicity. (C) 2016 Elsevier B.V. All rights reserved.