Despite recent advances in treatment, overall survival rates for metastatic melanoma, especially those that invade the lungs, continue to be low, with 5-year survival rates of only 3% to 5%. It was recently discovered that Wnt/β-catenin signaling pathways and MAPK/ERK signaling pathways are involved in melanoma metastasis.Methods:Herein, a bifunctional supramolecular peptide termed HBBplus@CA was constructed by a self-assembling RGD-modified MAPK/ERK peptide inhibitor (HBBplus) and a small molecule catenin inhibitor (carnosic acid (CA)).Results:Expectedly, the HBBplus@CA could internalize melanoma cells, accumulate in the tumor-bearing lung, and be biosafe. As designed, HBBplus@CA simultaneously suppressed both Wnt/β-catenin and MAPK/ERK signaling pathways and suppressed melanoma cell proliferation, migration, and invasion in more action than CA or HBBplusmonotherapy. More importantly, HBBplus@CA demonstrated potent inhibition of lung metastasis in mice bearing metastatic melanoma of B16F10 and significantly prolonged their survival.Conclusion:In summary, a supramolecular peptide-based strategy was not only developed to suppress pulmonary metastasis of melanoma, but it also renewed efforts to identify cocktail drugs that act on intracellular targets in various human diseases, including cancer.