Adenovirus-mediated gene transfer has application to the treatment of diseases of the central nervous system. We demonstrate that a limitation to its use in vivo is an inability to redose to the brain. We show that one factor inhibiting re-dosing is the development of neutralizing anti-adenoviral antibodies. Encapsulation of recombinant adenovirus vectors in poly(lactic/glycolic acid) (PLGA) copolymer enables infection in vitro, in the presence of neutralizing antibodies and results in the release of viable virus for over 100 h. Importantly, encapsulated adenovirus also shows diminished immunogenicity in vivo. Mice immunized with encapsulated recombinant adenoviral vectors show a greater than 45-fold reduction in anti-adenovirus titers relative to non-encapsulated vectors. An extended release formulation of adenovirus that reduces viral immunogenicity and sequesters the viral particle form antibody exposure may improve in vivo efficacy.