Shigellosis, acute inflammatory bacillary dysentery diseases, is an important agent in the mortality of children in developing countries. Annually 165 million people are being infected leading to 1.2 million deaths around the world. Although vaccination appears to be the only rational prophylactic approach to control shigellosis, currently, there is no safe and efficacious vaccine available in the market. Here in this study, we investigated the protection conferred by a new vaccine based on nanoparticles containing outer membrane vesicles (OMVs) of Shigella sonnei in an experimental model of shigellosis in mice. OMVs extracted by deoxycholate detergent were encapsulated in chitosan-TPP nanoparticles prepared by an ion gelation method and coated with an enteric polymer (NP-OMVs). NP-OMVs were spherical and homogeneous with a mean size of 344.7 nm (PdI = 0.2). BALB/c mice (females, 9-week-old, 25 ± 1 g) were immunized intraperitoneally (i.p.) with 20 µg of OMVs or by intragastric route (i.g.) with 50 µg of free or encapsulated OMVs. The protein concentrations of OMVs were 0.65 mg/mL and 1.02 mg/mL for bacteria grown at 37 ̊C and 42 ̊C respectively. OMVs loaded into nanoparticles were homogeneous and spherical, with a size of 344 nm. The encapsulation efficiency of NP was 85%. Antibody titers in immunized mice sera after 78 days revealed a persistent immune response. Free OMVs were able to protect against infection when it was administered by the intraperitoneal route. Oral administration of NP-OMVs showed better protection whereas free OMVs did not protect against infection. The results obtained in this research place OMVs among promising candidates to be used for vaccination.