Systemic iRGD homes to and penetrates the tumor tissue using a multistep mechanism (Figure 2A): (1) iRGD is recruited to tumor vessels by interaction of its RGD motif with αvβ3 and αvβ5 integrins on tumor cells and tumor endothelial cells; (2) The peptide is then proteolytically processed by a tumor-associated protease to C-terminally expose the active CendR motif, CRGDK; (3) the CRGDK fragment of iRGD then binds to NRP-1 to trigger transcytosis cascade that leads to deep penetration of peptide into the tumor tissue (Figure 2A–C). The gene discussed is NRP1; the disease is neoplasm.