Poly-L-Histidine Functionalized Boron Nitride Nanosheets as pH-Responsive Nanocarriers for Temozolomide Delivery: A Combined DFT and MD Study

The clinical effectiveness of temozolomide (TMZ), a common chemotherapeutic drug, is often limited by early hydrolytic breakdown, inadequate site-specific buildup, and off-target release. To overcome these issues, we propose a novel drug delivery system that utilizes hexagonal boron nitride (h-BN) nanosheets functionalized with poly-L-histidine (PLH), leveraging h -BN's high loading capacity and PLH's pH-responsive properties. Using a combination of density functional theory (DFT) and molecular dynamics (MD) methods, we carefully examined how TMZ adsorbs, remains stable, and is released from both pristine and PLH-functionalized BN surfaces. DFT calculations showed strong non-covalent interactions between TMZ and the nanocarrier, with interaction energies from -19.87 to -55.64 kcal/mol. Non-Covalent Interaction (NCI) and Quantum Theory of Atoms in Molecules (QTAIM) analyses confirmed that van der Waals forces, π–π stacking, and hydrogen bonds primarily stabilize the drug–carrier complex, with PLH functionalization significantly increasing binding strength. MD simulations further indicated a high TMZ loading capacity of 90% , with reduced solvent exposure in PLH-functionalized systems, where hydrogen bonding and electrostatic interactions contributed to stable drug retention. Importantly, under acidic conditions that mimic the tumor microenvironment, protonation of PLH led to effective TMZ desorption, with complex-3 showing the higher adsorption energy and better release profiles. Overall, these results highlight PLH-coated boron nitride as a promising pH-sensitive nanocarrier platform that offers efficient drug loading, stability in physiological conditions, and targeted release in acidic environments. This dual functionality provides a logical strategy to improve TMZ-based chemotherapy and could be applied to other hydrophilic anticancer agents.