After repeated frustrations with amyloid beta(Aβ)-targeted clinical trials for Alzheimer's disease(AD)in recent years,the therapeutic focus of AD has gradually shifted from Aβ to tau protein.The misfolding and aggregation of tau protein into neurofibrillary tangles(NFTs)cause neuron death and synaptic dysfunction,and the deposition of NFTs is more closely related to the severity of AD than Aβ plaques.Thus,it has great potential to target tau protein aggregation for AD treatment.The hexapeptide VQIVYK(known as PHF6)in tau protein has been found to play a dominant role for tau aggregation and was widely used as a model to design tau protein aggregation inhibitors.Here,inspired by natural heat shock protein(HSPs),we fabricated a self-assembly nanochaperone based on mixed-shell polymeric micelle(MSPM)as a novel tau-targeted AD therapy.With tunable phase-separated microdomains on the surface,the nanochaperone could effectively bind with PHF6 aggregates,inhibit PHF6 aggregation,block neuronal internalization of PHF6 species,thus significantly alleviating PHF6 mediated neurotoxicity.Moreover,the as-prepared nanochaperone could work with proteinase to facilitate the degradation of PHF6 aggregates.This bioinspired nanochaperone demonstrated a new way to target tau protein and provided a promising strategy for AD treatment.

Lin Zhu;Ming-Qing Zhang;Hao-Ren Jing;Xi-Peng Zhang;Lin-Lin Xu;Ru-Jiang Ma;Fan Huang;Lin-Qi Shi

State Key Laboratory of Medicinal Chemical Biology,Key Laboratory of Functional Polymer Materials of Ministry of Education,College of Chemistry,Nankai University,Tianjin 300071,China;Nankai University School of Medicine,Nankai University,Tianjin,China Department of Colorectal Surgery,Tianjin Union Medical Center,Tianjin 300074,China;Department of Colorectal Surgery,Tianjin Union Medical Center,Tianjin 300121,China;Key Laboratory of Radiopharmacokinetics for Innovative Drugs,Chinese Academy of Medical Sciences,and Institute of Radiation Medicine,Chinese Academy of Medical Sciences&Peking Union Medical College,Tianjin 300192,China

高分子科学（英文版）

[1]Lin Zhu;Ming-Qing Zhang;Hao-Ren Jing;Xi-Peng Zhang;Lin-Lin Xu;Ru-Jiang Ma;Fan Huang;Lin-Qi Shi-.Bioinspired Self-assembly Nanochaperone Inhibits Tau-Derived PHF6 Peptide Aggregation in Alzheimer's Disease)[J].高分子科学（英文版）,2022(09):1062-1070

Nanochaperone,frustrations,hexapeptide,VQIVYK,nanochaperone,MSPM

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