Graphene oxide-chitosan nanocomposites for phenethyl isothiocyanate delivery in glioma.

Hydrophobic drug delivery remains a major challenge in nanomedicine due to poor aqueous solubility, weak carrier-drug interactions, and uncontrolled in vivo distribution. Phenethyl isothiocyanate (PEITC), a hydrophobic anticancer agent currently under clinical investigation, exhibits low bioavailability and off-target toxicity, necessitating improved carrier strategies. Previous studies have explored graphene oxide-based formulations (GO-PEITC) for PEITC delivery; however, the role of chitosan-modified graphene oxide in regulating PEITC behavior through interfacial interactions has not been systematically examined. In this work, we utilize a covalently assembled graphene oxide-chitosan (GOCS) nanocomposite formed through amide coupling to enable controlled interfacial interactions with PEITC that govern its intracellular availability and bioactivity. PEITC interacts strongly with the GOCS matrix through a combination of electrostatic attraction, hydrogen bonding, and π-π interactions, resulting in efficient molecular retention and protection within the nanocomposite structure. Compared with unmodified graphene oxide, chitosan-functionalized graphene oxide acts as an active interfacial regulator, modulating surface charge, colloidal stability, and interlayer interactions to promote cooperative π-π stacking and polymer-mediated confinement of PEITC, leading to a stabilized GOCS-PEITC nanocomposite with enhanced drug-loading efficiency and pH-responsive release under acidic tumor-mimicking conditions. As a result, GOCS-PEITC exhibits improved intracellular delivery, induces β-tubulin destabilization, γ-H2AX-expression, apoptosis, and broad proteomic pathway modulation, and achieves superior tumor growth inhibition with favorable systemic biocompatibility in a subcutaneous glioma model.