Colorectal cancer (CRC) is the third most common tumor in the world and the second leading cause of cancer-related deaths. Despite improvements in screening and treatment that considerably reduced the occurrence and death rates over the last fifty years, CRC metastases remain a burden, with a survival rate of only 10% among affected patients. Traditional therapies often fail to penetrate effectively the tumor mass and selectively target it. For this purpose, nanoparticle-based treatments have attracted attention as a promising tool for cancer therapy to restrictively target biomarkers over-expressed by tumor, enabling the development of targeted strategies. In this study, zinc-oxide nanoparticles were synthesized and coated with a lipidic shell to enhance their biocompatibility; exploiting the maleimide-thiol chemistry, an optimized protocol was developed to conjugate the YSA peptide, proven for its selective affinity towards the Epha2 receptor, commonly over-expressed in the CRC cells.