Disease-Stage Synchronized Nanozyme Therapy for Polymicrobial Sepsis through Adaptive Catalytic and Immune Reprogramming.

Summary

The authors developed MICP@HG, a pH-adaptive nanozyme that changes its function during sepsis progression. It promoted cuproptosis-like bacterial killing in acidic infectious environments, then shifted toward superoxide dismutase- and catalase-like antioxidant activity and macrophage reparative reprogramming as inflammation resolved. The platform eradicated multidrug-resistant bacteria, preserved organ function, produced complete survival in polymicrobial sepsis models, and generated vaccine-like trained immunity.

Key Findings

• MICP@HG displayed peroxidase-like antibacterial activity and cuproptosis-like bacterial killing in acidic infectious microenvironments.
• As the microenvironment normalized, the nanozyme shifted toward superoxide dismutase- and catalase-like antioxidant and anti-inflammatory functions.
• The platform reduced systemic inflammation, preserved organ function, achieved complete survival in polymicrobial sepsis models, and conferred protection against reinfection through trained immunity.

Clinical Implications

The platform provides a potential framework for precision treatment of polymicrobial and multidrug-resistant sepsis, particularly when simultaneous infection control and prevention of inflammatory organ injury are required. Translation will require pharmacokinetic, toxicity, biodistribution, manufacturing, and large-animal studies before human trials.

Limitations

• The evidence is based on preclinical sepsis models and does not establish efficacy or safety in humans.
• The abstract does not provide detailed information on sample sizes, randomization, blinding, dose optimization, or long-term toxicology.

Future Directions

Future studies should validate biodistribution, pharmacokinetics, immunological durability, resistance development, and organ-specific toxicity in large-animal models, followed by carefully designed first-in-human studies.