Pegylated Graphene Oxide For 4′‐Fluorouridine Delivery: An Ab Initio Approach to Antiviral Therapy

Abstract Effective antiviral drug delivery systems, such as for 4′‐Fluorouridine (4′‐FlU), are crucial for addressing viral infections like COVID‐19. This study used ab‐initio analysis to examine interactions between 4′‐FlU and graphene oxide (GO)‐based carriers, with and without polyethylene glycol (PEG) functionalization, across various physiological conditions. Non‐PEGylated GO showed strong gas‐phase binding (−103.36 kcal mol −1 ), supporting systemic stability, while PEGylation reduced aqueous‐phase binding (−33.72 kcal mol −1 ), enhancing biocompatibility and circulation. Adsorption energies were significant in acidic and alkaline environments, with PEGylation intensifying alkaline interactions (−118.42 kcal mol −1 ). Charge transfer dynamics, influenced by pH and PEGylation, revealed enhanced stability under acidic conditions, suitable for tumor microenvironments. Hydrogen bonding stabilized GO‐drug complexes, ensuring prolonged release. PEGylated GO excelled in acidic environments, especially for tumor delivery, as confirmed by miscibility studies and controlled release kinetics. Thermodynamic and quantum chemical analyses highlighted environmental factors and PEGylation in optimizing stability and reactivity. GO/PEG‐4′‐FlU is ideal for localized drug delivery in acidic tumors, while GO/4′‐FlU supports systemic delivery requiring broader dispersion. This research lays the groundwork for nanotechnology‐based antiviral strategies and the design of adaptable drug delivery systems for both systemic and localized applications.