Simultaneous Removal of Endotoxin and Circulating Histones by Heparin-Grafted Chitosan-Cellulose Composite Microspheres for Multitargeted Hemoperfusion in Septic Blood

Endotoxin and circulating histones form a pathogenic loop, driving immune dysregulation in sepsis. A multitargeted extracorporeal blood purification combining endotoxin adsorption with histone neutralization may represent a critical therapeutic approach to improve the clinical outcomes of septic patients. However, existing hemoperfusion adsorbents are often heparin-dependent and single-target and exhibit limited hemocompatibility. Herein, we developed self-anticoagulant heparin-grafted chitosan/cellulose composite microspheres (CSCEHEP) for the simultaneous adsorption of endotoxin and circulating histones. The obtained CSCEHEP microspheres significantly prolonged plasma coagulation time while maintaining excellent hemocompatibility, owing to the heparin coating. In vitro, CSCEHEP microspheres exhibited adsorption capacities of 251.0 EU/g (81.8% clearance) for endotoxin and 288.6 μg/g (62.8% clearance) for histones, respectively. Meanwhile, CSCEHEP microspheres effectively adsorbed histones in whole blood and counteracted histone-induced endothelial and kidney epithelial cytotoxicity, erythrocyte fragility, and thrombocytopenia. In conclusion, CSCEHEP microspheres are promising adsorbents for hemoperfusion to simultaneously remove endotoxins and circulating histones in septic blood.