Engineered hollow Prussian blue nanoparticles for synergistic anti-inflammatory therapy in sepsis

Sepsis is a systemic inflammatory response triggered by pathogenic infections, often accompanied by bacterial endotoxin release, accumulation of cell-free DNA (cfDNA), and excessive inflammatory reactions, leading to organ failure. Conventional antibiotic therapies are often inadequate in effectively eliminating pathogens and their toxic components, and fail to suppress the cfDNA-mediated inflammatory cascade. In this study, we developed a multifunctional nanotherapeutic platform based on hollow Prussian blue nanoparticles (HPB-NPs) loaded with polymyxin E (PME) and surface-modified with polyethylenimine (PEI). This versatile nanosystem (HPB-NPs@PME@PEI) exhibits potent antimicrobial activity against Gram-negative bacteria and specifically neutralizes lipopolysaccharides (LPS); PEI captures elevated levels of LPS and cfDNA in septic blood via electrostatic adsorption, thereby blocking its activation of the TLR4/MyD88 pathway and mitigating the cytokine storm; meanwhile, HPB scavenges reactive oxygen species (ROS), alleviating oxidative stress damage. Experimental results demonstrate that HPB-NPs@PME@PEI significantly reduces plasma cfDNA levels, suppresses the release of pro-inflammatory cytokines, and improves survival rates in a murine sepsis model. HPB-NPs@PME@PEI directly suppress LPS-induced inflammatory activation and NETosis in innate immune cells. Furthermore, by scavenging ROS and blocking the TLR4/MyD88/NF-κB pathway, HPB-NPs@PME@PEI effectively protects lung and renal epithelial cells from LPS injury. Thus, the nano-system operates via a synergistic mechanism, concurrently neutralizing LPS, clearing ROS, and inhibiting a major inflammatory signaling cascade.