() is recognized as among the most critical bacterial pathogens globally. A significant portion of the complications associated with infections arises from its ability to persist inside host phagocytes, particularly macrophages, making the eradication of intracellular vital for therapeutic success. Regrettably, many antibiotics exhibit limited penetration into cells, underscoring the necessity for efficient intracellular delivery mechanisms. In this study, vancomycin-loaded chitooligosaccharide nanoparticles (COS@Van) coated with hyaluronic acid (HA), were engineered to function as an active-targeting antibiotic carrier recorded as HA/COS@Van. The HA coating serves as an external shell, which 1) covers the positive surface charge of COS NPs, thereby enhancing their biocompatibility and extending circulation time, and 2) facilitates targeted delivery to macrophages through specific interactions with the CD44 receptor. Confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) experiments confirmed that HA/COS could effectively accumulate in methicillin-resistant (MRSA) infected macrophages. Additionally, when administered intravenously in mouse models, HA/COS demonstrated markedly increased accumulation in the liver, the primary location of infected macrophages. These findings highlight the active-targeting capabilities of HA/COS both and settings. Consequently, after being loaded with Van, HA/COS@Van exhibited superior efficacy in killing intracellular MRSA , as compared to free Van. Furthermore, HA/COS@Van also demonstrated enhanced bactericidal activity in both mouse acute peritonitis model and mouse organ infection model. Therefore, this active-targeting delivery system may hold promise in advancing therapeutic outcomes for infections related to intracellular pathogens.