Tau-Targeted Multifunctional Nanoinhibitor for Alzheimer's Disease.

With the failure of various amyloid-β-targeted drugs for Alzheimer's disease (AD) in clinical trials, tau protein has gained growing attention as an alternative therapeutic target in recent years. The aggregation of tau exerts neurotoxicity, and its spreading in the brain is associated with increasing severity of clinical symptoms for AD patients; thus tau-targeting therapies hold great potential against AD. Here, a tau-targeted multifunctional nanoinhibitor based on self-assembled polymeric micelles decorated with tau-binding peptide is devised for AD treatment. Through the multivalent binding effect with the aggregating protein, this nanoinhibitor is capable of efficiently inhibiting tau protein aggregation, recognizing tau aggregates, and blocking their seeding in neural cells, thus remarkably mitigating tau-mediated cytotoxicity. Moreover, the formed nanoinhibitor-tau complex after binding is more easily degraded than mature tau aggregates, which will be conducive to enhance the therapeutic effect. We believe that this multifunctional nanoinhibitor will promote the development of new antitau strategies for AD treatment.