Chitosan/DNA-poly(sodium-4-styrenesulfonate) microspheres for hemoadsorption of histones: Synergistic integration of charge repulsion via phase inversion and in situ crosslinking

Circulating histones are critical inflammatory mediators that drive hyperinflammation and organ failure in critical illnesses such as sepsis, acute kidney injury, and acute respiratory distress syndrome. Their plasma levels are significantly correlated with disease severity and mortality in such patients. Although both DNA and sulfonic acid-containing macromolecules bind histones via electrostatic interactions, the primary challenge in integrating these antagonists into a unified anti-histone system lies in their mutual water solubility and similar negative charges. Herein, we fabricate novel chitosan/DNA-poly(sodium-4-styrenesulfonate) porous microspheres (C3D1-PSS) by employing a stepwise strategy involving phase inversion and subsequent in situ crosslinking polymerization. With a high-density, negatively charged histone capture network, the C3D1-PSS microspheres exhibit excellent hemocompatibility and achieve a notable histone adsorption ratio of 86.47% within 2 h and 95.52% within 4 h through synergistic electrostatic interactions mediated by phosphate and sulfonate groups in vitro. Furthermore, the C3D1-PSS microspheres significantly mitigate histone-induced thrombocytopenia, platelet activation, hemolysis, cytokine release, and endothelial cell death. In a histone-induced rabbit sepsis model, the C3D1-PSS microspheres efficiently alleviate histone-induced thrombocytopenia, tissue damage, hyperinflammation, and cell apoptosis. Collectively, this work presents a promising adsorbent for extracorporeal removal of histones and holds potential for managing histone-associated critical illnesses.