TA-Zr/Ce Nanozyme-Mediated Lipopolysaccharide Dephosphorylation: A Targeted Strategy for Sepsis Treatment with...

Sepsis is a life-threatening inflammatory syndrome caused by bacterial infections, with limited therapeutic options in critical care. Lipopolysaccharide (LPS) from Gram-negative bacteria triggers sepsis by activating toll-like receptor 4 (TLR4) through myeloid differentiation protein-2 (MD-2) binding. The phosphate groups in LPS serve as key recognition elements for this interaction. This study developed a zirconium/cerium (Zr/Ce) dual-metal nanozyme with phosphatase activity that catalyzes LPS dephosphorylation, disrupting LPS-TLR4 binding to inhibit NF-κB signaling and reduce inflammation. The nanozyme incorporated l-arginine and tannic acid (TA) to enhance the LPS binding capacity, while TA modification improved the antioxidant capability, constructing a multifunctional TA-Zr/Ce nanozyme. Results show that the nanozyme effectively catalyzes LPS dephosphorylation and suppresses inflammatory cytokine release from macrophages. In septic mice, TA-Zr/Ce treatment improved organ function, reduced systemic inflammation, and increased survival rates while promoting anti-inflammatory M2 macrophage polarization. Furthermore, this study constructed a regenerated cellulose microsphere (RCM)-based hemoperfusion system for loading nanozymes and efficiently removing LPS from blood, demonstrating strong clinical translation potential. Therefore, this research provides additional approaches and tools for the clinical management of sepsis.