<p>Targeting multiple neoepitopes by vaccines have the potential to circumvent intratumor clonal heterogeneities and minimize the chance of tumor escape. Due to immunostimulatory properties of outer membrane vesicles, their ability to target lymph nodes, as well as unaltered conformation of the loaded antigens in recombinant OMVs (rOMVs), they offer as promising vaccine platforms. Herein, we aimed to evaluate the therapeutic and antimetastatic potential of ClearColi^TM-derived rOMV_{CT−26 polytope} encoding CT-26 polytope and compare the induced immunity by the CT-26 polytope as a recombinant protein or as rOMV_{CT−26 polytope}. Herein, BALB/c mice were challenged subcutaneously by CT-26 cells and treated with OMV, rOMV_{CT−26 polytope}, CT-26 polytope, CT-26 polytope + rOMV_{CT−26 polytope}, CT-26 polytope + alum. Lung metastasis was evaluated in treated mice after intravenous CT-26 challenge. Treatment with CT-26 polytope + rOMV_{CT−26 polytope} resulted in the highest level of specific IgG2a titer and the greatest IFN-γ/IL-10 and TNF-α/IL-10 ratios, demonstrating their superior capacity to induce Th1 immunity. rOMV_{CT−26 polytope} alone or in combination with CT-26 polytope resulted in substantial tumor growth delay, and complete prevention of lung metastasis. In contrast, CT-26 polytope + alum and CT-26 polytope elicited higher IgG1 levels, a Th2-biased response, lower IFN-γ/IL-10 and TNF-α/IL-10 ratios. Moreover, despite fewer lung metastases than PBS in the CT-26 polytope-treated group, CT-26 polytope couldn’t completely suppress lung metastasis. Altogether, delivery of poly-neoepitopes by rOMV_{CT−26 polytope} resulted in considerable anti-tumor and antimetastatic effect in CT-26 therapeutic colon carcinoma model compared to its application as recombinant protein and consequently showed potential as personalized therapeutic CRC vaccines.</p>