Synergistic anticancer effects of carrier-free self-assembled doxorubicin and emodin nanoparticles in non-small cell lung cancer.

To develop excipient-free carrier-free nanoparticles (DE NPs) via self-assembly of doxorubicin (DOX) and emodin (EMO) for enhanced combination chemotherapy against non-small cell lung cancer (NSCLC). DE NPs were fabricated through non-covalent interactions between DOX and EMO using a self-assembly method. The nanoparticles were characterized for morphology, stability, encapsulation efficiency, and cellular uptake. In vitro cytotoxicity and in vivo antitumor efficacy of free drugs (EMO, DOX), DOX/EMO mixture, and DE NPs were evaluated on A549 NSCLC cells. Mechanistic studies explored the role of DE NPs in suppressing efflux pump proteins via modulation of p65 activation and nuclear translocation. DE NPs formed rod-like nanostructures with high encapsulation efficiency (> 90%) and stability. They exhibited enhanced cellular uptake and intracellular drug accumulation compared to free drugs or the mixture. In vitro studies demonstrated significantly stronger cytotoxicity in A549 cells (IC50 reduction of ~ 50%) and a synergistic antitumor effect (combination index < 0.5). In vivo studies further confirmed the superior antitumor efficacy of DE NPs over individual DOX or EMO monotherapy (72.67 ± 7.20% tumor inhibition rate). Mechanistically, DE NPs inhibited p65 activation and nuclear translocation, downregulating efflux pump protein expression and prolonging drug retention in cancer cells. The excipient-free DE NPs provide a promising carrier-free nanomedicine platform for NSCLC treatment, achieving synergistic antitumor efficacy through enhanced drug delivery and suppression of drug resistance mechanisms. This strategy highlights the potential of self-assembled dual-drug nanoparticles to improve therapeutic outcomes in combination.