Neutrophils loaded NAD⁺ impede TLR4/NF-κB/NLRP3 pathway for sepsis treatment

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Sepsis Therapeutics

Background:

• Sepsis causes multi-organ dysfunction through systemic inflammation, excessive reactive oxygen species (ROS), and mitochondrial impairment.
• Current sepsis treatments targeting single mechanisms are insufficient.
• A precision nanodrug delivery system is needed for effective sepsis therapy.

Purpose of the Study:

• To design and evaluate a neutrophil-targeting nanodrug delivery system (MSe-NAD+/Nes) for sepsis treatment.
• To mitigate inflammation and organ dysfunction by addressing ROS and mitochondrial impairment.
• To enhance NAD+ levels and restore mitochondrial function.

Main Methods:

• Developed a precision nanodrug delivery system (MSe-NAD+/Nes) using mesoporous selenium nanozymes (MSe NPs) and a neutrophil-targeting strategy.
• Investigated the ROS-triggered release of NAD+ from MSe NPs.
• Assessed the ROS scavenging activity of MSe NPs, mimicking glutathione peroxidase (GPx).
• Evaluated the system's efficacy in vivo for sepsis treatment.

Main Results:

• MSe-NAD+/Nes successfully delivered drugs to inflammatory sites.
• Released NAD+ replenished cellular NAD+ pools, restoring mitochondrial function.
• MSe NPs effectively eliminated ROS, preventing NLRP3 inflammasome activation.
• In vivo studies showed reduced organ oxidative stress, restored ATP levels, and attenuated hyperinflammation.
• The system facilitated rapid organ repair in sepsis models.

Conclusions:

• The MSe-NAD+/Nes system offers a promising therapeutic strategy for sepsis.
• It effectively combats sepsis-induced organ dysfunction by scavenging ROS and repairing mitochondria.
• This approach provides a reliable and safe modality for inflammation remission in sepsis.