RGD-functionalized ultrasmall ceria nanozymes ameliorate sepsis via dual modulation of inflammatory cascades and gut microbiota dysbiosis

Sepsis, a dysregulated host response to infection causing life-threatening organ dysfunction, remains a critical global healthcare challenge with mortality rates persisting at 30-50 % despite advances in critical care. Current treatments fail to address the disease's complex pathophysiology, particularly the critical role of gastrointestinal tract dysfunction and gut microbiota dysbiosis in driving systemic inflammation. This study presents a novel therapeutic approach using RGD-functionalized cerium oxide nanoparticles (RCeO₂ NPs), engineered to combine targeted delivery, ROS scavenging, and microbiota modulation. Through a scalable nano self-assembly approach, we developed RCeO₂ NPs with optimized ligand density and surface charge, validated for physicochemical properties, hemocompatibility, and ROS-neutralizing capacity. In a lipopolysaccharide-induced murine sepsis model, RCeO₂ NPs demonstrated dual efficacy in suppressing proinflammatory cytokines (IL-1β, TNF-α) while restoring gut microbial equilibrium, correlating with improved survival rates and intestinal barrier integrity. An innovative ecotoxicological assessment using Biomphalaria glabrata confirmed the biosafety of RCeO₂ NPs. This work advances a promising therapeutic strategy for sepsis treatment and provides a blueprint for designing multifunctional nanomedicines that bridge immune and microbial axes of disease.