Functionalized graphene oxide (CGO–cRGDyK/POLO) nanosheets were designed and developed for targeted drug delivery to integrin expression. The anticancer drug cambretastain A4 (CA4) was conjugated onto the CGO–cRGDyK/POLO nanosheets. The tumor targeting ligands, cyclic arginine–glycine–aspartic acid–tyrosine–lysine pentapeptides (cRGDyK), were conjugated to carboxylated graphene oxide (CGO) nanosheets, and poloxamer 188 (POLO) was rendered to make the CGO–cRGDyK nanosheets stable. The CGO–cRGDyK/POLO nanosheets exhibited good cytocompatibility, high CA4-loading capacity (0.6872 ± 0.0121 mg mg⁻¹) via π–π stacking or hydrophobic interactions, and controlled release in vitro. The MTT assays showed that the CGO–cRGDyK nanosheets had greater antitumor effects on Hela cells than CGO/POLO nanosheets but lower cytotoxicity on the L02 cells than free CA4. In addition, the cellular uptake of CGO–cRGDyK/POLO nanosheets was increased significantly in human umbilical vein endothelial cells (the integrins-overexpressed cells) compared to the normal L02 cells. Thus, the CGO–cRGDyK/POLO nanosheets are an appealing platform for cancer chemotherapy.