Engineering a pathological tau-targeted nanochaperone for selective and synergetic inhibition of tau pathology in Alzheimer's Disease

Tau-targeting therapies for Alzheimer’s disease (AD) have received increasing attention in recent years, due to the clinical failure of various anti-amyloid β drugs and closer association between tau burden and cognitive impairments in AD patients. The intracellular tau aggregation is recognized as a vital event in tau pathway of AD progression. However, current developed tau aggregation inhibitors are still facing serious challenges on how to access the cytosol of cells where tau protein mainly located and differentiate pathological tau from normal tau. Herein, we report a customized biomimetic nanochaperone for targeting intracellular pathological tau, serving as a novel anti-tau therapy of AD. This nanochaperone was tailored by engineering VQIINK hexapeptide derived from tau protein onto the surface of self-assembly micelle equipped with chaperone-like hydrophobic microdomains and confined spaces. With the lysosomal microenvironment responsiveness of unique surface structure, the Tau-nChap can escape from lysosome and enter into cytoplasm to overcome the intracellular tau location challenge. More importantly, the cytosol-arrived nanochaperone can selectively capture pathological tau without interfering with normal tau and potently inhibit their aggregation through the synergic effect of tau-recognizing peptide and confined hydrophobic microdomain on surface. As a result, the tau-targeting nanochaperone rescues neuronal cells from tau-mediated neurotoxicity and ameliorates cognitive deficits of AD model mice. Therefore, we believe that this custom-built tau-nanochaperone represents a promising weapon for combating AD and provides valuable insights for the treatment of other neurodegenerative disorders induced by specific pathogenic proteins including Parkinson’s disease and Huntington’s disease.