Tau Amyloid Corona-Shelled Nanoparticle-Based Drug Screening Platform for Discovering Tau Oligomer-Degrading Drugs

Tau oligomers have been known to play a crucial role in neuronal toxicity and synaptic dysfunction in a heterogeneous group of neurodegenerative diseases collectively known as tauopathies. However, the discovery of drugs that specifically target tau oligomers has been impeded by the lack of appropriate screening methods. Here, we suggest a drug screening platform based on tau amyloid corona-shelled nanoparticles (TACONs) to assess the efficacy of tau oligomer-degrading compounds through aggregation-induced colorimetric responses of TACONs. TACONs were engineered via the encapsulation of gold nanoparticles with homogeneous tau oligomers by leveraging heparin as a co-factor. Further, to validate the proposed strategy, we employed tau oligomer-degrading proteases (protease XIV and plasmin) and various small molecules that have been demonstrated to aid in the treatment of tauopathies. We demonstrated that the proposed strategy with TACON can discover tau oligomer-degrading agents, thereby potentially reducing the attritive problem encountered in drug discovery for tauopathies.