Multi-targeted biomimetic CeO₂-based nanoplatform for sepsis therapy via mitochondrial homeostasis

Sepsis is a life - threatening systemic inflammatory response syndrome triggered by pathogenic infections, which is characterized by severe oxidative stress, immune dysregulation, and multiple organ dysfunction, accompanied by a high mortality rate. Its primary pathogenesis encompasses pathogen - induced immune overactivation, resulting in cytokine storms, oxidative damage, tissue injury, and organ failure. This research developed a bionic nanotherapeutic system for the treatment of sepsis. Cerium dioxide (CeO₂) nanoparticles with inherent antioxidant activity were employed as carriers, loaded with the broad - spectrum antibiotic imipenem - cilastatin sodium hydrate (IC), and further coated with macrophage membranes (MM). The MM conferred immune evasion, homologous targeting, and lipopolysaccharide (LPS) - neutralizing capabilities to the nanosystem.This integrated platform combines CeO₂ - mediated reactive oxygen species (ROS) scavenging, antibiotic - induced bactericidal effects, and MM - mediated inflammatory regulation. In vitro investigations verified its potent ROS - scavenging, LPS - neutralizing, anti - inflammatory, and antibacterial activities. In a cecal ligation and puncture (CLP) - induced mouse sepsis model, IC@CeO₂@MM effectively reduced both systemic and local inflammatory cytokines, alleviated multi - organ injury in the liver, kidneys, and intestines, and enhanced survival rates. Mechanistically, it maintained mitochondrial membrane potential and decreased mitochondrial ROS (mtROS) accumulation in macrophages.This synergistic strategy simultaneously achieves antibacterial, antioxidant, and immunomodulatory effects, presenting a promising and novel approach for the comprehensive management of sepsis.