Abstract Bacterial infection is a major threat to public health. Nanotechnology offers a solution by combining nanomaterials with antibacterial agents. The development of an effective nanocomposite against drug‐resistant bacteria such as methicillin‐resistant Staphylococcus aureus (MRSA) is highly important yet challenging. Here, an anti‐MRSA core–shell structure is designed, containing antibacterial zeolitic imidazolate framework‐8 (ZIF‐8) as the core and bactericidal benzalkonium chloride (BAC) templated rough‐surface mesostructured silica nanocomposite (RMSN) as the shell. The resultant ZIF‐8@RMSN nanocomposite exhibits sustained release of BAC and zinc ions, effective disruption of the bacterial membrane, generation of oxidative damage of bacterial DNA, leakage of intracellular components, and finally bacterial death. Furthermore, the synergistic antibacterial mechanisms lead to enhanced biofilm elimination performance. In addition, the ZIF‐8@RMSN‐modified band‐aid effectively combats MRSA infection in vivo. This work has provided a promising nanocomposite against MRSA‐related infections.
