Herpes simplex virus type-2 (HSV-2) is a common cause of genital infections throughout the world. Currently no prophylactic vaccine or therapeutic cure exists against the virus that establishes a latent infection for the life of the host. Intravaginal microbivac is a developing out-of-the-box strategy that combines instant microbicidal effects with future vaccine-like benefits. We have recently shown that our uniquely designed zinc oxide tetrapod nanoparticles (ZOTEN) show strong microbivac efficacy against HSV-2 infection in a murine model of genital infection. In our attempts to further understand the antiviral and immune bolstering effects of ZOTEN microbivac and to develop ZOTEN as a platform for future live virus vaccines, we tested a ZOTEN/HSV-2 cocktail and found that prior incubation of HSV-2 with ZOTEN inhibits the ability of the virus to infect vaginal tissue in female Balb/c mice and blocks virus shedding as judged by plaque assays. Quite interestingly, the ZOTEN-neutralized virions elicit a local immune response that is highly comparable with the HSV-2 infection alone with reduced inflammation and clinical manifestations of disease. Information provided by our study will pave the way for the further development of ZOTEN as a microbivac and a future platform for live virus vaccines.