Prussian Blue Nanozyme Disrupts the Self-Reinforcing Loop of Tauopathy via Triple-Action Mechanism.

Abstract

Tauopathies, such as Alzheimer's disease, are driven by a self-reinforcing pathological triad of tau aggregation, oxidative stress, and autophagy dysfunction, which remains inadequately addressed by single-target therapies. Herein, we engineer an ultrasmall Prussian blue nanozyme (PBzyme) as a multienzyme-mimetic and multi-target agent to concurrently disrupt this vicious cycle. PBzyme functions as a potent tau fibril inhibitor, with molecular dynamics simulations revealing high-affinity binding to β-sheet domains (-400 kJ/mol), thereby reducing tau phosphorylation and hippocampal burden. In parallel, PBzyme acts as a multifunctional antioxidant enzyme mimic, efficiently neutralizing •OH, O₂ ^-, and H₂O₂ to alleviate oxidative injury. Furthermore, PBzyme restores autophagic flux by activating AMPK/ULK1 signaling while inhibiting the mechanistic target of rapamycin (mTOR), thereby promoting the clearance of tau aggregates. In an okadaic acid-induced tauopathy rat model, PBzyme treatment effectively preserved synaptic integrity, suppressed neuroinflammation, mitigated neuronal loss, and rescued cognitive deficits. Notably, PBzyme enters cells to counteract intracellular tau and ROS, overcoming a key limitation of conventional biologics. This work establishes PBzyme as an integrated nanoagent offering a synergistic therapeutic strategy against tauopathies and other ROS-related neurodegenerative diseases.