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Objective To investigate the ability of specific polyclonal antibodies against Staphylococcus aureus (S. aureus) lipoprotein SA2275 to penetrate the blood-brain barrier for inhibiting the formation of S. aureus-induced brain abscess in mice. Methods We immunized BALB/c mouse mice with purified recombinant S. aureus lipoprotein SA2275 expressed in Escherichia coli to obtain specific mouse polyclonal antibodies against SA2275 (anti-SA2275). In a C57BL/6 mouse model of brain abscess induced by injecting S. aureus strain Newman into the brain, we tested the titer of anti-SA2275 in the brain tissue using ELISA following intraperitoneal injection of the antibodies to evaluate the ability of the antibodies to pass through the blood-brain barrier. The bacterial load in the mouse brain was determined by gradient dilution bacterial counting, and the size of the brain abscess was evaluated on serial sections. Results The recombinant SA2275 protein with a high purity was successfully obtained. The results of ELISA showed that immunization of the mice with the recombinant SA2275 protein resulted in a high titer of anti-SA2275 reaching 1:51 200. In the mouse models of S. aureus-induced brain abscess, the presence of the antibodies was detected in the brain tissue after intraperitoneal injection of anti-SA2275. Treatment with anti-SA2275, as compared with blank control mouse serum, significantly reduced the size of the brain abscess and lowered the bacterial load in the brain tissues of the mice. Conclusion In mouse models of S. aureus-induced brain abscess, intraperitoneally injected lipoprotein SA2275-specific antibodies can penetrate the blood-brain barrier to reach the brain tissue and inhibit the formation of brain abscess and bacterial colonization, suggesting the potential of the antibodies for treatment of S. aureus-induced brain abscess.