Rational Design of B, Ge, Mg, and Si-Decorated Al₁₂N₁₂ Nanocages from Composite Density Functional Theory Insight: Toward Efficient Memantine Nanocarrier Design for Alzheimer’s Therapy

Memantine (MMT) is widely prescribed to slow the progression of Alzheimer's disease. Yet, its effectiveness is limited because the drug is partially lost before reaching the central nervous system due to absorption barriers in the gastrointestinal tract and the blood–brain barrier. For this reason, developing an efficient nanomaterial-based drug delivery system (DDS) is essential, and the Al₁₂N₁₂ nanocage emerges as a promising platform. In this study, the interactions between MMT and pristine as well as B-, Ge-, Mg-, and Si-decorated Al₁₂N₁₂ nanocages were examined using DFT at the r²SCAN-3c level in both gas and solvent environments to better represent physiological conditions. The adsorption behavior was evaluated through structural and thermodynamic analyses, electronic structure characterization (FMO, DOS, UV–Vis), and topological interaction analyses (QTAIM, NCI-RDG, IRI, IGMH, ESP). The results show that while doping does not significantly change the nanocage geometry, it reduces the band gap and modifies electronic properties. A critical finding is the phase-dependent dopant switching: Al₁₂N₁₂Ge–MMT achieves the strongest gas-phase adsorption (E_ads = −366.23 kJ/mol), while Al₁₂N₁₂Mg–MMT becomes superior in the aqueous phase (E_ads = −196.97 kJ/mol), reflecting solvation-induced electronic reorganization. Memantine adsorption proceeds spontaneously through an exothermic mechanism via partial covalent and van der Waals interactions, with favorable solvation thermodynamics and favorable recovery times. Electronic analyses indicate charge redistribution and bond formation characteristic of charge-transfer-driven binding. These findings identify pristine and decorated Al₁₂N₁₂ nanocages as promising theoretical candidates for memantine drug delivery, warranting further experimental investigation.