D-Penicillamine/Dihydroquercetin Dual-Loaded Metal–Organic Framework as a Microenvironment Copper Regulator for Enhancing the Therapeutic Efficacy of Polyphenolic Antioxidant in Alzheimer’s Disease

Polyphenols like dihydroquercetin, rutin, and rifampicin show promise for Alzheimer’s disease (AD) therapy due to their ability to inhibit amyloid-β (Aβ) aggregation and reduce reactive oxygen species (ROS), garnering significant recent interest. However, their efficacy is substantially diminished because excess metal ions present in amyloid plaques can chelate these compounds. Therefore, reshaping the metal microenvironment in the patient’s brain is particularly important for the therapeutic effect of AD. To address the above issues, we have constructed a composite system formed by NH2-MIL-101(Fe) (MOF), dihydroquercetin (DHQ), and D-penicillamine (D-pen). Due to the lack of π-π interaction and the low adsorption energy between D-pen/MOF, the release order and speed of D-pen was much faster than DHQ, thus achieving metal microenvironment regulation and ensuring the therapeutic effect of DHQ. In a 5 × FAD transgenic mouse model, DD@MOF treated and improved spatial learning and memory deficits. Therefore, the DD@MOF based on polyphenolic compounds provides a potential research direction for intervention in Alzheimer’s disease through chelating copper ions and antioxidant properties.