LAUSR

Biofilms are the primary form of infections caused by bacterial pathogens such as Pseudomonas aeruginosa (P. aeruginosa). Encased in extracellular polymeric substances, biofilms form a sealed, dense, and hypoxic microenvironmental barrier, limiting antibiotic penetration, impairing ROS‐based sonodynamic therapy (SDT), and resulting in persistent and recurrent infections. Here, ultrasound‐triggered nano‐bomb (UNB) is developed to comprehensively eradicate biofilms. The UNB consists of polymyxin B (PMB)‐functionalized liposomes encapsulating the sonosensitizer IR780 and oxygen‐carrying perfluorobromooctane (PFOB). PMB enables targeted delivery to P. aeruginosa, while oxygen‐loaded PFOB generates seed bubbles that initiate inertial cavitation under ultrasound stimulation. This process creates intense mechanical forces that disrupt the biofilm structure and rupture the liposomes, releasing IR780 and oxygen. In both superficial wound and internal deep‐seated pulmonary infection models, UNB demonstrates potent anti‐biofilm and bactericidal effects while reducing inflammation. This work highlights the effectiveness of leveraging mechanical forces generated by inertial cavitation, rapidly initiated through the artificial introduction of seed bubbles, to disrupt biofilm barriers. Further, combine oxygen delivery to reverse the anaerobic microenvironment within the biofilm to enhance the efficacy of SDT. This approach offers a novel and promising paradigm for enhanced mechano‐sonodynamic therapy to solve complex P. aeruginosa‐associated biofilm infections.