Ce-myricetin nanoparticles alleviate inflammation and multi-organ damage through ROS clearance and macrophage reprogramming in sepsis

Sepsis remains a life-threatening condition associated with substantial mortality, driven by pathological elevations in reactive oxygen species (ROS), uncontrolled inflammatory responses, and impaired immune homeostasis. In this study, we developed novel cerium (Ce) and myricetin-based nanoparticles (Ce-Myr NPs) for the synergistic treatment of sepsis. The nano-system neutralized excess ROS, while Ce-Myr NPs synergistically downregulated the expression of pro-inflammatory factors via the inhibition of Toll-like receptor 4-myeloid differentiation primary response 88-nuclear factor kappa-B (TLR4-MyD88-NF-κB) signaling and significantly alleviated sepsis by the dual pathway. Ce-Myr NPs could remodel macrophage polarization, promote differentiation of the M2 anti-inflammatory phenotype, and inhibit the M1 pro-inflammatory phenotype. These dual-functional nanoparticles demonstrated superior ROS-neutralizing efficiency and immunoregulatory performance in vitro, effectively alleviating oxidative damage and inducing macrophages to develop anti-inflammatory profiles. In a mouse sepsis model induced by cecal ligation and puncture, systemic delivery of Ce-Myr NPs significantly improved survival rates, reduced multi-organ damage, and decreased systemic inflammation, as indicated by low pro-inflammatory cytokine levels. The optimized Ce-Myr NPs exhibited excellent biosafety profiles and robust reactive species scavenging capabilities, highlighting their potential as a multimodal therapeutic platform for sepsis management and related oxidative stress pathologies.