Effective inhibition of lung metastatic melanoma by pH-responsive lipopeptide/PLGA hybrid nanoparticles silencing PD-L1 with augmented suppression of the AKT/β-catenin pathway.

Boosting immune response has been extensively used for improving the inhibition of metastatic melanoma with immune checkpoint inhibitors (ICIs). However, its efficacy has been largely counteracted by complicated immune escape mechanisms and immune-related adverse events. To address these challenges, we presented a new approach for effective inhibition of lung metastatic melanoma (LMM) by augmented suppression of the AKT/β-catenin pathway. The pH-responsive C-pArg-pHis lipopeptide/PLGA hybrid nanoparticles (SLNPs) were developed to complex with PD-L1 siRNA (siP) and encapsulate hydrophobic resveratrol (Res). The pH-responsive pHis accelerated the payload release and induced the endosomal escape of siP through the "proton sponge" effect. Res/siP@SLNP showed a significant inhibitory effect on the migration ability of B16F10 cells , which was attributed to the synergistic suppression of the AKT/β-catenin pathway during epithelial-mesenchymal transition (EMT). SLNP loaded with siP (siP@SLNP) showed a significantly stronger LMM inhibition than the control group in immunosuppressed mice, indicating the involvement of suppression of the AKT/β-catenin pathway instead of the immune response mediated by PD-1/PD-L1 blockade. Res/siP@SLNP certainly showed higher LMM inhibition than siP@SLNP in immunosuppressed mice due to the synergistic suppression of the AKT/β-catenin pathway the combination of Res and siP. Res/siP@SLNP showed the strongest inhibition of LMM in normal mice, which was attributed to a synergistic effect on the immune modulation and the suppression of the AKT/β-catenin pathway. In conclusion, augmented suppression of the AKT/β-catenin pathway has been demonstrated to be an effective approach to inhibit LMM, providing a potential strategy in combination with immune boosting.