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However, unsatisfactory efficacy, non\u2010targeted and imprecise treatment, along with interconnected pathogenic factors in AD, constrain the therapeutic efficacy of current AD therapeutic strategies. Herein, in lieu of complex multi\u2010module treatments for pathogenesis, a bespoke in situ activatable hydrogen\u2010bonded organic framework (HOF)\u2010based nanozyme (denoted as NADH@Pre\u2010Cu\u2010HOF@KD8) has been constructed to modulate multiple interconnected homeostatic imbalances in AD. Benefiting from the specific organic monomers, 2,2\u2032\u2010bipyridine\u20105,5\u2032\u2010dicarboxylic acid, NADH@Pre\u2010Cu\u2010HOF@KD8 can sequester neurotoxic Cu\n                    <jats:sup>2+<\/jats:sup>\n                    from amyloid\u2010\u03b2 (A\u03b2)\u2010Cu\n                    <jats:sup>2+<\/jats:sup>\n                    by competitive binding. The segregation of Cu\n                    <jats:sup>2+<\/jats:sup>\n                    from A\u03b2 mitigated the generation of reactive oxygen species, A\u03b2 toxicity, and alleviated the activation of microglia cells. Moreover, HOF\u2010based nanozyme possessed NADH peroxidase (NPX)\u2010like catalytic activity after binding Cu\n                    <jats:sup>2+<\/jats:sup>\n                    , which can reduce oxidative stress and elevate compromised NAD+ levels, thereby restoring mitochondrial impairment and adenosine triphosphate (ATP) production. Spatiotemporally precise intervention is enabled through targeted delivery mediated by peptide modification and lesion\u2010specific activation. Notably, cognitive deficits, neuropathology, and homeostatic markers in a 3xTg\u2010AD mouse model are ameliorated upon treatment. By employing a facile HOF platform to modulate multiple interconnected pathological homeostatic imbalances in AD\u2014copper toxicity, NAD\u207a depletion, oxidative stress, and A\u03b2 toxicity\u2014this strategy offers a paradigm for ameliorating AD\u2010associated homeostatic imbalances.\n                  <\/jats:p>","DOI":"10.1002\/smll.202509547","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T11:14:48Z","timestamp":1763723688000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["In Situ Activatable Hydrogen\u2010Bonded Organic Framework\u2010Based Nanozyme as NADH Peroxidase Mimic Restoring Homeostasis for Treatment of Alzheimer's Disease"],"prefix":"10.1002","volume":"22","author":[{"given":"Haochen","family":"Zhang","sequence":"first","affiliation":[{"name":"Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization Changchun Institute of Applied Chemistry Chinese Academy of Sciences  Changchun Jilin 130022 P. 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