Phage‐Inspired Nanomotor Synergized with Sono‐Sensitive Antibiotics for Treating Multidrug‐Resistant <i>Klebsiella pneumoniae</i> Lung Infection

Abstract Biofilm‐associated refractory pneumonia represents a growing clinical challenge, where the protective extracellular matrix not only confers drug resistance but also promotes persistent infections. While topologically structured physical bactericidal systems show potential for biofilm disruption, their reliance on passive diffusion limits penetration efficiency, and biofilm regeneration following treatment remains problematic. Inspired by phage invasion mechanisms, a biohybrid nanomotor integrating sono‐sensitive antibiotics is developed for combating multidrug‐resistant Klebsiella pneumonia (MDR‐KPN)‐induced lung infections. The asymmetric heterostructured nanomotor consists of hollow mesoporous Prussian blue‐lomefloxacin/mesoporous Cu x O (CuO/Cu 2 O composite) Janus nanoparticle (HP‐L/MCu JNPs), which can actively target and dismantle biofilms through integrated mechanical and chemical action. The innovative design of nanomotor leverages two complementary functionalities: Cu x O nanospheres provide autonomous propulsion for mechanical biofilm penetration, and the Prussian blue subunit enables ultrasound‐triggered antibiotic release; meanwhile, ultrasound‐activated antibiotics generate cytotoxic singlet oxygen ( 1 O 2 ) that induces irreparable DNA damage in surviving bacteria. Transcriptomic analysis confirms this combined mechanical‐chemical action effectively disperses biofilms while preventing bacterial recovery. In vivo validation demonstrates the therapeutic potential of this biomimetic strategy, which merges physical destruction with catalytic chemistry to overcome biofilm‐associated treatment resistance. This approach establishes a new paradigm for addressing persistent bacterial infections through integrated nanoarchitectonics.