Disrupting Biofilm Tolerance by Ionic Microbubble-Mediated Copper Ion Surge for Infection Clearance

Abstract

Bacterial infections caused by drug-resistant bacteria persist due to biofilm-mediated tolerance, which limits the efficacy of both antimicrobial agents and host immune defenses. Here, we develop ionic microbubbles (MB-CuTA) self-assembled by Fe₃O₄@CuTA nanoparticles to enhance copper ion-mediated antibiofilm therapy. Upon ultrasound activation, MB-CuTA undergoes inertial cavitation, disrupting biofilm integrity and generating a localized surge of copper ions. This process achieves a dual therapeutic effect: (1) disruption of bacterial metabolic homeostasis, thereby overcoming the intrinsic resistance of biofilms to conventional antimicrobial agents, and (2) activation of cellular immunity to effectively counteract bacterial immune evasion mechanisms. By breaking biofilm tolerance through both metabolic and immunological pathways, our strategy enables deep copper ion penetration in biofilms and effective infection clearance in both mouse implant infection and peritonitis infection models. Our approach introduces a biofilm tolerance disruption method through inducing bacterial cuproptosis-like death and cellular immunity activation, offering a promising strategy against biofilm infections.