DFT‐Guided Design of Hydroxytyrosol‐Encapsulated Nanocages: Comparative Insights into Boron Nitride Versus Carbon Fullerenes for Targeted Drug Delivery and Therapeutic Applications

Abstract Hydroxytyrosol (HT), a bioactive compound in olive oil, has therapeutic potential but is limited by low bioavailability and instability. This study explores fullerene‐like nanocages (B₁₂N₁₂, B₁₆N₁₆, C₂₄, C₃₂) as nanocarriers to enhance HT delivery. Using DFT, QTAIM, and molecular docking, interactions between HT and nanocages are analyzed. Boron nitride nanocages, particularly B₁₂N₁₂, show the strongest binding (Eads = −25.28 kcal mol −1 in water) via Lewis acid‐base interactions, improving stability (ΔG = −11.90 kcal mol −1 ) and solubility. Carbon cages (C₂₄, C₃₂) exhibit weaker van der Waals interactions (Eads = −7.42 to −10.24 kcal mol −1 ), favoring controlled release. Electronic analyses reveal altered HT reactivity upon complexation. QTAIM confirms partially covalent B─O bonds in (BN) n = 12, 16 ‐HT systems, while carbon cages rely on dispersive forces. UV–vis spectra show redshifted peaks for BN‐HT complexes, indicating enhanced delocalization. Molecular docking demonstrates improved therapeutic effects of HT‐nanocage complexes. For instance, C₂₄‐HT strongly bound to COVID‐19 protease (E Dc = −3.86 kcal mol −1 ) and HER2 kinase (E Dc = −3.99 kcal mol −1 ), enhancing antiviral and anticancer activity. Similarly, B₁₆N₁₆‐HT effectively targets TNF‐α (E Dc = −3.70 kcal mol −1 ), showing superior anti‐inflammatory effects. These findings highlight nanocarriers' potential to overcome HT's limitations, enabling advanced biomedical applications.