Carbon Nitride Covalent Organic Frameworks With Wide Porosity as Potential Drug Carrier Surfaces

ABSTRACT The targeted drug delivery system (TDDS) offers an advanced therapeutic strategy by improving drug efficiency, adsorption, and safety. In this study, the carbon nitride (C 4 N) nanosheet was evaluated as a potential carrier for hydroxyurea (HU) and mesalamine (MES). The adsorption characteristics of both drugs on the C 4 N surface were investigated using non‐covalent interaction (NCI), quantum theory of atoms in molecules (QTAIM), electron density difference (EDD), natural bond orbital (NBO), and frontier molecular orbital (FMO) approaches. MES exhibited slightly stronger adsorption on C 4 N than HU, with BSSE‐corrected interaction energies of −23.39 kcal/mol for HU@C 4 N and −28.33 kcal/mol for MES@C 4 N. NCI and QTAIM analyses indicate that van der Waals interactions play a key role in stabilizing both complexes. NBO and EDD reveal significant charge transfer, while FMO analysis shows a larger HOMO–LUMO gap for MES@C 4 N, suggesting enhanced electronic stability. Additionally, dipole moment variations, pH‐dependent behavior, and molecular dynamics simulations also support the stable binding and controlled release of MES. Steered molecular dynamics (SMD) and umbrella sampling reveal a controlled detachment of MES with a free energy barrier of ∼15–16 kJ/mol. This moderate energy barrier suggests favorable adsorption with efficient release, highlighting the potential of C 4 N as an effective drug delivery carrier.