A Self-Assembled Metabolic Regulator Reprograms Macrophages to Combat Cytokine Storm and Boost Sepsis Immunotherapy.

Summary

This preclinical study identifies crosstalk between the itaconate–STING axis and glycolysis in macrophage inflammation and introduces a self-assembled nanoparticle (LDO) that co-targets both pathways. LDO reprograms macrophage polarization, reduces CCL2-driven cytokine storms, ameliorates acute lung injury, and improves survival in sepsis models.

Key Findings

• Discovered functional crosstalk between the itaconate–STING axis and glycolysis in macrophage-mediated inflammation.
• Engineered a self-assembled nanoparticle (LDO) combining 4-octyl-itaconate with lonidamine to co-target STING signaling and glycolysis.
• In murine sepsis models, LDO attenuated CCL2-driven cytokine storms, reduced acute lung injury, and significantly improved survival.

Clinical Implications

Although preclinical, the work supports developing dual-target immunometabolic agents for sepsis. If safety and pharmacokinetics are favorable, such agents could complement antimicrobial and organ support by damping cytokine storm without broad immunosuppression.

Limitations

• Preclinical animal data; human safety, pharmacokinetics, and efficacy are unknown.
• Sepsis models may not capture the heterogeneity and comorbidities of human sepsis.

Future Directions

Conduct dose-ranging, toxicology, and pharmacokinetic studies; assess efficacy in polymicrobial sepsis and immunocompromised models; explore combination with antibiotics and organ support; evaluate biomarkers of response.