Bioorthogonal Polymer Nanozymes for Effective Treatment of Bacterial Wound Biofilm Infections

Multidrug-resistant (MDR) bacterial infections are a rapidly emerging healthcare crisis. The challenge of MDR bacteria is further exacerbated through biofilm formation that limits effective drug penetration and hinders the ability of the host immune system to clear the infection. Cationic polymer nanoparticles carrying bioorthogonal transition-metal catalysts (polyzymes) can penetrate bacterial biofilms and locally catalyze the uncaging of antimicrobial drug derivatives, acting as an in situ bioorthogonal "drug factory". Polyzymes were designed and fabricated using an amphiphilic polymer nanoscaffold and iron(III) tetraphenyl porphyrin as the catalyst. The polyzyme bioorthogonally uncaged an azide-protected prodrug of the antimicrobial drug moxifloxacin. The efficacy of this approach was tested in vitro against an in vitro Escherichia coli (E. coli) biofilm, resulting in a ∼3.5-log10 colony-forming units (CFU/mL) reduction of bacterial load (99.99%). The polyzyme was subsequently incorporated into a thermoresponsive Poloxamer 407 hydrogel to create a wound dressing, and the localized activation of pro-moxifloxacin was tested in an in vivo E. coli wound biofilm model. The polyzyme-mediated localized activation of the prodrug was highly effective, resulting in significantly more bacterial killing compared to the free drug moxifloxacin. These results demonstrate the therapeutic potential of bioorthogonal polyzymes for treating wound biofilm infections, with enhanced local activity and improved treatment outcomes compared to standard clinical treatment methods.