A ROS-responsive nanoprodrug-engineered phage biotherapy for precision treatment of multidrug-resistant Gram-negative...

Area of Science:

• Nanotechnology and Drug Delivery
• Antimicrobial Resistance
• Bacteriophage Therapy

Background:

• Multidrug-resistant Gram-negative bacteria (MDR-GNB) are a major cause of severe pneumonia, with limited treatment options.
• Polymyxins are effective against MDR-GNB but face challenges due to toxicity and resistance development.
• Targeted drug delivery systems are needed to improve antibiotic efficacy and reduce side effects.

Purpose of the Study:

• To develop and evaluate a biohybrid therapeutic platform combining a polymyxin B-prodrug nanosystem with an engineered phage.
• To assess the targeted delivery, efficacy, and safety of this platform in a bacterial pneumonia model.

Main Methods:

• Construction of a biohybrid nanoplatform integrating a polymyxin B-prodrug with an engineered bacteriophage.
• In vitro characterization of the nanosystem's drug release mechanism triggered by reactive oxygen species (ROS).
• In vivo evaluation in a mouse model of bacterial pneumonia to assess lung distribution, pathogen elimination, and inflammation reduction.

Main Results:

• The phage-prodrug nanoplatform demonstrated robust lung distribution and tissue retention.
• The system effectively eliminated MDR-GNB pathogens, reduced oxidative damage, and alleviated inflammation.
• Reactive oxygen species (ROS) at inflamed sites triggered targeted release of polymyxin B.

Conclusions:

• The phage-prodrug biohybrid nanoplatform offers a promising strategy for targeted antibiotic delivery against MDR-GNB.
• This approach enhances therapeutic efficacy while potentially mitigating polymyxin-associated toxicities.
• The study presents a novel paradigm for combating infectious diseases caused by multidrug-resistant pathogens.