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Herein, we engineer an ultrasmall Prussian blue nanozyme (PBzyme) as a multienzyme\u2010mimetic and multi\u2010target agent to concurrently disrupt this vicious cycle. PBzyme functions as a potent tau fibril inhibitor, with molecular dynamics simulations revealing high\u2010affinity binding to \u03b2\u2010sheet domains (\u2212400 kJ\/mol), thereby reducing tau phosphorylation and hippocampal burden. In parallel, PBzyme acts as a multifunctional antioxidant enzyme mimic, efficiently neutralizing \u2022OH, O\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    , and H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    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\u2013induced 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\u2010related neurodegenerative diseases.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202505286","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T07:13:59Z","timestamp":1773040439000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prussian Blue Nanozyme Disrupts the Self\u2010Reinforcing Loop of Tauopathy via Triple\u2010Action Mechanism"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5174-6377","authenticated-orcid":false,"given":"Fei","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine Zhejiang Cancer Hospital Hangzhou Institute of Medicine Chinese Academy of Sciences  Hangzhou China"},{"name":"Department of Nuclear Medicine and PET Center The Second Affiliated 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