Metallated Graphitic Carbon Nitride as a High˗Affinity Nanocarrier for Curcumin in Alzheimer's Disease Therapy: A DFT Study

ABSTRACT Curcumin, a natural polyphenol with neuroprotective potential for Alzheimer's disease (AD), suffers from limited bioavailability due to poor solubility and rapid degradation. To address this, we employed dispersion‐corrected density functional theory (DFT‐D3, PBE0‐D3/def2‐TZVP) to investigate graphitic carbon nitride (gC 3 N 4 ) functionalized with Fe 2 + , Cu 2 + , and Zn 2 + as a nanocarrier for curcumin. Metallation of the gC 3 N 4 heptazine cavity significantly enhances curcumin adsorption, with energies increasing from −43.93 kcal mol −1 for pristine gC 3 N 4 to −122.32 to −144.30 kcal mol − 1 upon metal incorporation. This enhanced binding arises from bidentate M–O coordination through curcumin's keto‐enol moiety and cooperative O―H···N hydrogen bonds with the gC 3 N 4 framework. The Fe 2 + ‐functionalized system exhibits the strongest adsorption (−144.30 kcal mol − 1 ), surpassing Cu 2 + and Zn 2 + analogues. In aqueous solution (SMD model), adsorption energies remain robust (−56.29 to −90.10 kcal mol − 1 ), suggesting that metallated gC 3 N 4 is a promising nanocarrier for improving curcumin's stability and delivery under physiological conditions. These findings provide a theoretical basis for designing advanced nanocarriers for AD and other therapeutic applications, and highlight experimentally testable predictions, such as isothermal titration calorimetry, spectroscopic binding studies, and in vitro release assays under physiological and pH‐varied conditions.