Exploring the interaction of doxorubicin with silica surface for targeted drug delivery using density functional theory

Doxorubicin (DOX) is a widely used chemotherapeutic agent, but its clinical efficacy is limited by severe side effects and drug resistance. Silica-based nanoparticles (SiNPs) offer a promising solution for targeted drug delivery due to their biocompatibility, high surface area, and tunable porosity. Non-covalent interactions (NCI) analysis confirms stronger hydrogen bonding in Fe-doped systems whereas Co-doped surfaces enable more efficient charge redistribution. Band structure and density of states (DOS) calculations reveal enhanced electronic coupling in Fe₄@SiO₂ (overlap integral S ≈ 0.28) compared to Co₄@SiO₂ (S ≈ 0.19), suggesting superior interfacial charge transfer. Molecular dynamics simulations further validate the stability of DOX@Fe₄@SiO₂ (RMSD: 2.5–3.0 Å) and pH-dependent charge fluctuations (Bader net charge: −0.1 to −0.05 |e|). The reduced optical gaps in metal-doped systems (0.71–0.85 eV) enhance electronic coupling, promoting drug stability via charge delocalization, improving transport efficiency through potential light-triggered mechanisms, and increasing targeting accuracy by facilitating pH-responsive release in tumor environments. These findings provide a mechanistic basis for designing silica-based nanocarriers with optimized drug-loading capacity, pH-triggered release, and reduced off-target toxicity, advancing precision oncology therapeutics.