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

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 Cu²⁺ from amyloid-β (Aβ)-Cu²⁺ by competitive binding. The segregation of Cu²⁺ 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 Cu²⁺, 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.