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The purpose of the present study was to identify an “easy-to-adopt” strategy to enhance immune responses using functionalized alginate (ALG) nanoparticles (MAN-ALG/ALG=OVA NPs), which were prepared by CaCl2 cross-linking of two different types of ALG. The mannose (MAN) modified ALG (MAN-ALG) was used for dendritic cell targeting. The other component, composed of ovalbumin (OVA), a model antigen, is conjugated to ALG (ALG=OVA) via pH sensitive Schiff base bond. Grafting of alginate was demonstrated by FT-IR and 1H NMR, while the morphological structure, particle size, Zeta potential of MAN-ALG/ALG=OVA NPs were measured using TEM and DLS. The OVA releasing behavior of MAN-ALG/ALG=OVA NPs was determined as a function of pH. Antigen uptake was examined by flow cytometry and confocal laser scanning microscopy in vitro using mouse bone marrow dendritic cells (BMDCs). The results showed that MAN-ALG/ALG=OVA NPs facilitated antigen uptake of BMDCs and cytosolic release of the antigen. Significant up-regulation of cytokine secretion and expression levels of the surface co-stimulatory molecules were also observed in MAN-ALG/ALG=OVA NPs-treated BMDCs, compared to free OVA. In vivo bio-distribution study using Cy7 (a near-infrared fluorescence dye) labeled MAN-ALG/ALG=OVA NPs showed efficient in vivo trafficking of the nanoparticles from the injection site to the draining lymph nodes. Moreover, MAN-ALG/ALG=OVA NPs were found to enhance cross-presentation of OVA to B3Z T cell hybridoma in vitro. Subcutaneous administration of MAN-ALG/ALG=OVA NPs also induced major cytotoxic T lymphocytes (CTL) response and inhibition of E.G7 tumor growth in C57BL/6 mice. In summary, we report here that the MAN-ALG/ALG=OVA NPs have the potential as a potent nanovaccine for cancer immunotherapy.