Malignant tumors remain a leading cause of death and novel, specific, and effective therapies are urgently needed for several tumor types. Recombinant adeno-associated viruses (rAAV) provide well-characterized biological and structural features enabling tumor targeting at the capsid and at the genetic level. The epidermal growth factor receptor (EGFR) is a validated tumor marker addressed by several therapeutic antibodies. We explored the potential of rAAV for tumor therapy by rational insertion of a small antibody mimetic in the capsid and endowing them with a trans-gene encoding a prodrug-activating enzyme. The EGFR binding Affibody ZEGFR:1907 was genetically incorporated within the variable region IV (453-loop) of rAAV-VP2 of the serotypes AAV2 or AAV9. The respective mosaic rAAVs were produced successfully. We demonstrated EGFR-dependent binding and transduction in model cell lines (MCF7, HeLa, A431). Ultimately, patient derived neuroendocrine tumor cells were transduced and killed mediated by thymidine kinase expression and ganciclovir activation.