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Septicemia accounts for 20% of global mortality, mainly caused by dysregulation of excessive activation of macrophages, leading to imbalance in immune homeostasis. Existing anti-inflammatory strategies often impair the ability to clear pathogens and exacerbate immunosuppression. Precisely targeting over-activated macrophages while maintaining antibacterial function is a promising therapeutic approach. Through high-throughput screening of 390 kinase inhibitors, we discovered that the polo-like kinase 1 (PLK1) inhibitor GSK461364 is a potent regulator of hyperactivation. However, its clinical translation is limited by dose-dependent cytotoxicity and systemic toxicity. Therefore, we designed mannitol-functionalized nanoparticles (Nano-PLK1in) for targeted combination delivery of the inhibitor and glutathione to highly active macrophages. These nanoparticles significantly increased the uptake of hyperactivated macrophages in mice and humans, approximately twice that of cell uptake. The Nano-PLK1in platform achieved: (i) precise inhibition of the caspase-11 pathway through PLK1 blockade, (ii) reactivation of redox homeostasis through glutathione-mediated mitochondrial protection, (iii) maintaining antibacterial ability without extensive immunosuppression. In sepsis mouse models, Nano-PLK1in significantly increased survival rate by 50%, reduced coagulation dysfunction by 41.8%, and decreased ALT/creatinine levels by 28.9–54.3%, reflecting organ protection and enhanced bacterial clearance. By combining precise macrophage reprogramming with effective pathogen elimination, our nanoscale engineering strategy overcomes the efficacy-to-toxicity trade-off of traditional therapies and highlights its translational potential in sepsis treatment.
This study was published in ACS Nano under the title "An Engineered Triple-Functional Nanoplatform for Effective Sepsis Therapy via Macrophage-Targeted Polo-like Kinase 1 Inhibition". References:
DOI: 10.1021/acsnano.5c20947
