Nucleotide coordinated polymers, a ROS-based immunomodulatory antimicrobial, doubly kill Pseudomonas aeruginosa biofilms of implant infections

<i>Pseudomonas aeruginosa</i> causes high morbidity and mortality in nosocomial infections, and newly approved antibiotics have been declining for decades. A green and universal deprotonation-driven strategy is used to screen the guanylic acid-metal ion coordination polymer nanoparticles (GMC), instead of the failure of binding occurs when specific metal ion participation. We find that the precise pH-dependent oxidase-like activity of GMC-2 orchestrates a duple symphony of immune modulation for <i>Pseudomonas aeruginosa</i> biofilm infections. Specifically, GMC-2-mediated reactive oxygen species (ROS) regulation triggers mitochondrial dysfunction and releases damage-associated molecular patterns, engaging pattern recognition receptors and resulting in endogenous innate immune activation. Meanwhile, GMC-2-triggered ROS generation in a mildly acidic biofilm environment destroys the biofilm, exposing exogenous pathogen-associated molecular patterns. GMC-2 cannot cause resistance for <i>Pseudomonas aeruginosa</i> compared with conventional antibiotics. In an infected implant mouse model, <i>Pseudomonas aeruginosa</i> biofilms were effectively eliminated by GMC-2-mediated triggering of innate and adaptive immunity. These findings provide a universal approach for facilitating the binding of biomolecules with metal ions and highlight the precise ROS-regulating platform plays a critical role in initiating endogenous and exogenous immune activation targeted for bacterial biofilm infection.