Oncolytic Ad, which selectively replicate in cancer, is emerging as a promising new modality for the treatment of cancer and it has several advantageous attributes over non-replicating Ads. Oncolytic Ad possesses an inherent ability to multiply, lyse infected cancer cells, and spread to surrounding cells. The potency of oncolytic Ad is drastically improved by arming it with anticancer transgenes. These transgenes can inhibit oncogenic signaling pathways as well as normalizing the hostile and dysregulated microenvironmental factors of tumor like extracellular matrix, immune surveillance, and vascularization. Most prominent aspect of oncolytic Ad-mediated therapeutic gene expression is that the gene expression is greatly amplified through viral replication and occurs in cancer-specific manner, thus leading to high level of therapeutic gene expression in tumor tissues while being absent in normal tissues. 

Still, successful eradication of advanced and metastatic cancer requires systemically administrable viral vector system to efficiently target both primary tumors and metastases. As native tropism of Ad prevents successful systemic delivery of viral particles to tumor regions, we have investigated several nanomaterials for complexation with Ad to enhance the target-specific delivery of oncolytic Ad. These nanomaterials possess unique physicochemical properties that allow integration of multiple functionalities in a single design, which can be subsequently transferred to nanomaterial-complexed Ad hybrid vector system. We have demonstrated that multifunctional nanomaterial-coated Ad can be used to enhance intratumoral accumulation of Ad and restrict accumulation in nontarget tissues. Further, nanomaterial-coated oncolytic Ads is protected from hostile host environment, such as immune system and degradative enzymes, which leads to prolonged blood circulation and higher bioavailability of Ad in tumor tissues. Our findings demonstrate that efficient tumor-targeting by hybrid vector system can attenuate systemic toxicity of Ad by attenuating the hepatotoxicity, ectopic transgene expression at non-target tissues, and induction of immune response against Ad.