An Engineered Triple-Functional Nanoplatform for Effective Sepsis Therapy via Macrophage-Targeted Polo-like Kinase 1...

Area of Science:

• Immunology
• Nanotechnology
• Pharmacology

Background:

• Sepsis causes 20% of global deaths, driven by macrophage hyperactivation disrupting immune balance.
• Existing anti-inflammatory treatments risk pathogen clearance and increase immunosuppression.
• Targeting hyperactivated macrophages while maintaining antimicrobial function is a key therapeutic goal.

Purpose of the Study:

• To identify kinase inhibitors modulating macrophage hyperactivation.
• To engineer nanoparticles for targeted delivery of a PLK1 inhibitor and glutathione.
• To evaluate the efficacy and safety of the Nano-PLK1in platform in sepsis models.

Main Methods:

• High-throughput screening of 390 kinase inhibitors identified GSK461364 (PLK1 inhibitor).
• Mannose-functionalized nanoparticles (Nano-PLK1in) were engineered for dual delivery.
• In vitro and in vivo studies in murine and human hyperactivated macrophages and sepsis models were conducted.

Main Results:

• Nano-PLK1in enhanced cellular uptake by ~2-fold in hyperactivated macrophages.
• The platform inhibited the caspase-11 pathway, restored redox homeostasis, and preserved antimicrobial capacity.
• In murine sepsis models, Nano-PLK1in improved survival by 50%, reduced coagulopathy, protected organs, and enhanced bacterial clearance.

Conclusions:

• Nano-PLK1in offers a promising strategy to overcome the efficacy-toxicity trade-off in sepsis treatment.
• This nanoscale engineering approach enables precision macrophage reprogramming and pathogen eradication.
• The study highlights the translational potential of Nano-PLK1in for managing sepsis.