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The silk-elastinlike protein polymer, SELP 815K, and poloxomer 407, a commercially available synthetic copolymer, were evaluated to compare their relative performance in matrix-mediated viral gene delivery. Using a xenogenic mouse tumor model of human head and neck squamous cell carcinoma, the efficacy of viral gene-directed enzyme prodrug therapy with these polymers was characterized by viral gene expression in the tumor tissue, tumor size reduction, and survivability with treatment. Viral injection in SELP 815K produced a greater level and more prolonged extent of gene expression in the tumor, a statistically greater tumor size reduction, a longer time until tumor rebound, and a significantly increased survivability, as compared to injection of virus alone or in Poloxamer 407. Safety of treatment with these polymers was evaluated in a non-tumor bearing immunocompetent mouse model. Compared to virus injected alone or in Poloxamer 407, virus injected in SELP 815K had fewer and less severe indications of toxicity related to treatment as assessed by blood analysis, body weight, and histopathology of distant organs and the injection sites. Similar to virus alone or in Poloxamer 407, virus injected in SELP 815K elicited a mild injection site inflammatory response characterized primarily by a mononuclear leukocyte infiltrate and the formation of granulation tissue. Virus injected in SELP 815K resulted in fewer animals with elevated white blood cell counts and a less pronounced local toxicity reaction than was observed with virus in Poloxamer 407. In contrast to virus injected alone or in Poloxamer 407, which were not retained in the injection site tissues beyond week 1, SELP 815K was retained at the injection sites and by the end of the study (week 12), displayed limited absorption, and mild encapsulation. These results demonstrate the benefits of SELP 815K for matrix-mediated gene delivery over the injection of free virus and the injection of virus in Poloxamer 407. Virus in SELP 815K had greater efficacy of tumor suppression, promoted greater levels and greater duration of viral gene expression, and displayed reduced levels of injection site toxicity. Combining these performance and safety benefits with the degree of control with which they can be designed, synthesized and formulated, SELPs continue to show promise for their application in viral gene delivery.