Buforin IIb and bilirubin co-loaded CeO₂nanoparticles mitigate sepsis-related encephalopathy via synergistic anti-inflammation and neuroprotection.

Sepsis, a dysregulated host response to infection causing life-threatening organ dysfunction, remains a leading cause of mortality worldwide with death rates exceeding 30%. Current therapeutic approaches inadequately address the complex pathophysiology involving uncontrolled cytokine release, oxidative stress, and persistent infection. Here we report cerium-based nanomodulators (CBB NPs) that integrate antioxidant, anti-inflammatory, and antimicrobial functions for synergistic therapy. The nanoplatform comprises hollow mesoporous cerium oxide nanoparticles (CeO₂ NPs) as catalytic cores, exploiting Ce3+/Ce4+ redox cycling to mimic superoxide dismutase (SOD) and catalase (CAT) enzymes for reactive oxygen species (ROS) scavenging. Bilirubin (BR) provides additional antioxidant protection, while antimicrobial peptide Buforin IIb confers antimicrobial activity. In cecal ligation and puncture (CLP) sepsis model, CBB NPs treatment improved 7-day survival from 0% to 60%, reduced pro-inflammatory cytokine release, and effectively cleared pathogen burden. Notably, CBB NPs ameliorated sepsis-related encephalopathy (SAE) by maintaining blood-brain barrier (BBB) integrity, promoting hippocampal neurogenesis, and improving cognitive dysfunction. This synergistic approach exhibits considerable therapeutic promise for sepsis and related neurological consequences, providing a model for addressing complex disorders via integrated nanomedicine techniques.