Molecular Insights into Paclitaxel and Curcumin-Loaded Carbon Dots: Computational and Experimental Evidence of NRF2 and Autophagy Modulation in Ovarian Cancer

Ovarian cancer remains a highly aggressive and deadly gynecological malignancy, primarily due to acquired chemoresistance. Curcumin, a natural compound with potent anticancer properties, is limited by poor bioavailability, hindering its clinical application. This study investigates nitrogen and boron codoped carbon dots (NBCDs) as a nanocarrier to enhance curcumin delivery and therapeutic efficacy against chemoresistant ovarian cancer. NBCDs were synthesized via a one-pot hydrothermal method and characterized for their physicochemical properties. We evaluated the cellular uptake and cytotoxic effects of curcumin-loaded NBCDs (CUR-NBCDs) and paclitaxel-loaded NBCDs (PTX-NBCDs) in OVCAR3 and SKOV3 ovarian cancer cell lines. Oxidative stress markers, autophagy induction, and NRF2 pathway modulation were analyzed using fluorescence microscopy, biochemical assays, and qPCR. Molecular docking and dynamics simulations were employed to study drug interactions with key autophagy regulatory proteins. Results demonstrated that NBCDs exhibit excellent biocompatibility and enhance curcumin's cellular uptake. CUR-NBCDs effectively induced autophagy, evidenced by acridine orange staining and modulation of autophagy markers. Molecular analysis revealed downregulation of NRF2 and P62, and upregulation of BECLIN1, indicating NRF2 pathway suppression and enhanced autophagic flux. Molecular docking and dynamics simulations confirmed stable interactions between curcumin and autophagy regulatory proteins. In conclusion, NBCDs enhance curcumin's bioavailability and therapeutic efficacy by modulating the NRF2-autophagy axis, offering a potential therapeutic approach to address ovarian cancer chemoresistance through dual targeting of oxidative stress and autophagy pathways.