In Situ Activatable Hydrogen‐Bonded Organic Framework‐Based Nanozyme as NADH Peroxidase Mimic Restoring Homeostasis for Treatment of Alzheimer's Disease

Abstract Nicotinamide adenine dinucleotide (NAD) serves as a vital regulator in metabolic networks, and the decrease in the level of its oxidized form, NAD+, is closely related to Alzheimer's disease (AD). However, unsatisfactory efficacy, non‐targeted 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‐module treatments for pathogenesis, a bespoke in situ activatable hydrogen‐bonded organic framework (HOF)‐based nanozyme (denoted as NADH@Pre‐Cu‐HOF@KD8) has been constructed to modulate multiple interconnected homeostatic imbalances in AD. Benefiting from the specific organic monomers, 2,2′‐bipyridine‐5,5′‐dicarboxylic acid, NADH@Pre‐Cu‐HOF@KD8 can sequester neurotoxic Cu ²⁺ from amyloid‐β (Aβ)‐Cu ²⁺ by competitive binding. The segregation of Cu ²⁺ from Aβ mitigated the generation of reactive oxygen species, Aβ toxicity, and alleviated the activation of microglia cells. Moreover, HOF‐based nanozyme possessed NADH peroxidase (NPX)‐like catalytic activity after binding Cu ²⁺ , 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‐specific activation. Notably, cognitive deficits, neuropathology, and homeostatic markers in a 3xTg‐AD mouse model are ameliorated upon treatment. By employing a facile HOF platform to modulate multiple interconnected pathological homeostatic imbalances in AD—copper toxicity, NAD⁺ depletion, oxidative stress, and Aβ toxicity—this strategy offers a paradigm for ameliorating AD‐associated homeostatic imbalances.