A biodegradable engineered nanoplatform combining anti-angiogenic activity and targeting of cancer cells to improve the anticancer activity of docetaxel (DTX) is here proposed. Indeed, we have developed biodegradable nanoparticles (NPs) of poly(ethylene glycol)-poly(ε-caprolactone), exposing on the surface both folate motifs (Fol) for recognition in cells overexpressing Folate Receptor- a (FRa) and the anti-angiogenic hexapeptide aFLT1. The presence of Fol on NPs did not impair the anti-angiogenic activity of aFLT1, as assessed by in vitro tube formation assay in HUVEC endothelial cells. In both 2D and 3D KB cell cultures in vitro , the cytotoxicity of DTX loaded in NPs was not significantly affected by Fol/aFLT1 double decoration as compared to free DTX. Remarkably, NPs distributed differently in 3D multicellular spheroids of FRa-positive KB cancer cells depending on the type of ligand displayed on the surface. When tested in vivo in zebrafish embryos xenografted with KB cells, NPs displaying Fol/aFLT1 reduced DTX systemic toxicity and inhibited in a synergistic way the growth of the tumor mass and associated vasculature. Overall, nanotechnology offers excellent ground for combining therapeutic concepts in cancer, paving the way to the development of novel multifunctional nanopharmaceuticals where surface decoration with bioactive elements can significantly improve therapeutic outcomes.