Due to self-produced extracellular polymeric substances (EPS), biofilms are hard to eradicate by common antimicrobials. Herein, a new quaternary ammonium salt based cross-linked micelle (QAS@CM) was created to combat biofilms. The QAS@CM adsorbed first onto the biofilm surface through multicharged interaction, then penetrated the EPS in the form of nanoparticles and diffused throughout the films. By responding to the biofilm acid/lipase microenvironment, these nanoparticles would further break into quaternary ammonium oligomers and act as the polyvalent inhibitors to effectively destroy the established biofilm and kill the corresponding bacteria within it.