Co‐Delivery of Cationic Polymeric Sonosensitizer and Antimicrobial Peptide Mimic by Polymeric Nanoparticle for Enhanced Therapy of Lethal Bacterial Pneumonia

ABSTRACT Pneumonia caused by multidrug‐resistant bacteria has emerged as a significant public health concern. To address this issue, this study develops an innovative inhalable polymeric nanoparticle SK5.3, which is constructed by encapsulating a cationic polymeric sonosensitizer CBODI‐2 and a cationic antimicrobial peptide mimic BriTE with an anionic, reactive oxygen species (ROS)‐sensitive, amphiphilic polymer HSJT. Ultrasound (US) stimulation triggers the sonodynamic effect of CBODI‐2 to generate 1 O 2 , which cleaves ROS‐sensitive scaffold within HSJT to induce nanoparticle dissociation and cargo release, but also directly cause bacterial killing. Cationic CBODI‐2 and BriTE, concurrently released from dissociated SK5.3, target negatively charged bacterial cell surfaces via electrostatic attractions. These enable SK5.3+US to execute a three‐mode attack synergistically combining membrane‐attacking P + Ph 3 Br − and BriTE, and sonodynamic effect, demonstrating the potent antibacterial efficacy against Klebsiella pneumoniae and Staphylococcus aureus both in vitro and in vivo. This therapeutic superiority stems from a dual mechanism involving not only direct bactericidal effect but also beneficial host immunomodulation—suppressing inflammation together with promoting injury repair. The nanotherapeutic platform SK5.3+US represents a highly effective strategy for antibiotic‐alternative treatment of refractory deep‐seated infections.