SDF-1/CXCR4 is one of the most relevant chemokine signaling pathways to cancer metastasis, and siRNA targeting CXCR4 may provide potential improvements to treat those highly metastatic cancers, especially when combined with chemotherapy. A riboflavin-modified lipo-polyplexes to co-deliver CXCR4 siRNA and doxorubicin (PhD/siRNA/lip-RF) were constructed conveniently by acid-sensitive cationic prodrug (PEI-hyd-DOX, PhD) condensed with anionic siRNA to form PhD/siRNA polyplexes, which were further coated with riboflavin-tailed lipid-membrane. The PhD/siRNA/lip-RF were effectively taken into tumor cells and inhibited primary tumor growth and tumor metastasis in vivo.