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

Sepsis accounts for 20% of global mortality, largely driven by dysregulated hyperactivation of macrophages that disrupts immune homeostasis. Current anti-inflammatory strategies often compromise pathogen clearance and exacerbate immunosuppression. Precisely targeting hyperactivated macrophages while preserving antimicrobial function represents a promising therapeutic approach. Through high-throughput screening of 390 kinase inhibitors in hyperactivated macrophages, we identified the polo-like kinase 1 (PLK1) inhibitor GSK461364 as a potent modulator of hyperactivation. However, its clinical translation is limited by dose-dependent cytotoxicity and systemic toxicity. To address this, we engineered mannose-functionalized nanoparticles (Nano-PLK1in) for targeted combinatorial delivery of the inhibitor and glutathione to hyperactive macrophages. These nanoparticles significantly enhanced cellular uptake, approximately 2-fold, in both murine and human hyperactivated macrophages. The triple-action Nano-PLK1in platform enables: (i) precision inhibition of the caspase-11 pathway via PLK1 blockade, (ii) reactivation of redox homeostasis through glutathione-mediated mitochondrial protection, and (iii) preservation of antimicrobial capacity without broad immunosuppression. In murine models of sepsis, Nano-PLK1in markedly improved survival by 50% compared to free drug, along with a 41.8% reduction in coagulopathy and a 28.9-54.3% decrease in ALT/creatinine levels reflecting multiorgan protection, and enhanced bacterial clearance. By integrating precision macrophage reprogramming with effective pathogen eradication, our nanoscale engineering strategy surmounts the efficacy-toxicity trade-off of conventional therapies, highlighting its translational promise for sepsis treatment.