Effective therapeutic approaches for treatment of metastatic or drug-resistant cancer remain an unmet medical need. The emerging oncolytic virotherapy, seeking to exploit the use of replication-competent viruses to destroy cancers, represents a unique strategy and holds great promise for cancer therapy. Clinical activities related to this method have increased considerably in the past decade; many trials are ongoing or have been completed using oncolytic viruses. Although several trials showed great promise when viruses were injected directly into tumor nodules leading to significant tumor shrinkage, systemic intravenous delivery is required for treatment of metastatic cancer, where tumor nodules are spread widely around the body. However, many oncolytic viruses which are effective when administrated intratumorally lack anticancer efficacy when administrated intravenously. The key reason for this is the rapid clearance of the viruses from the blood circulation via the immune system before they reach tumor sites. For oncolytic virotherapy, an adequate amount of intravenous virus delivery is critical for therapeutic success. To be effective, oncolytic viruses for systemic intravenous delivery need to possess adequate stability in blood to selectively target cancer cells and elicit tumor oncolysis. According to published accounts, CD47 self-marker protein with high expression on the surface of red blood cells and cancer cells was demonstrated to be a repressor of macrophage phagocytosis. In this study, we propose to conjugate the CD47-streptavidin fusion protein onto biotinylated viruses via biotin-streptavidin affinity. Various concentrations of soluble recombinant CD47-streptavidin fusion protein will be produced and quantitatively tethered on viruses that are biotinylated. The interaction of CD47-tagged viruses and macrophages will be investigated to understand the potential roles of CD47 in the regulation of immune evasion of functionalized viruses. Furthermore, polyethylene glycol will be conjugated along with CD47 protein to prevent phagocytosis and serum inactivation of functionalized viruses. In addition to its antiphagocytic feature, CD47 protein conjugated on the virus will act as a ligand specifically targeted for tumor cells that are highly expressed with αvβ3 integrins. The proposed strategy on labeling the model virus with CD47 protein and polyethylene glycol can be employed to various types of oncolytic enveloped viruses which are expected to have extended stability in blood circulation, thereby allowing for more efficient site-binding via αvβ3 integrin and improving the efficacy of cancer therapy.