Nanobody-based high-performance multitarget immunosorbents protect against sepsis by concurrently adsorbing endotoxins and inflammatory cytokines.

Abstract

Sepsis, a life-threatening disease caused by severe infections, affects over 40 million people worldwide annually, with high mortality rates in intensive care units. Bacterial endotoxins and cytokine storms induced by infection are two primary therapeutic targets for sepsis management. Recent advances in biomaterials have offered many promising opportunities for treating infectious and inflammatory diseases, particularly hemoperfusion adsorbents. However, simultaneously attenuating endotoxin levels and cytokine storms in whole blood directly by hemoperfusion remains clinically challenging due to the distinct physicochemical properties (charge and size) of endotoxins and cytokines. Herein, we report a multitarget immunosorbent designed to combat sepsis, constructed by conjugating an anti-tumor necrosis factor-α nanobody to l-arginine functionalized polystyrene resin (PS-Arg-Nb). This system provides abundant binding sites for both endotoxins and multiple cytokines while maintaining excellent biocompatibility. By concurrently and efficiently adsorbing endotoxins and inflammatory cytokines, the PS-Arg-Nb immunosorbent significantly reduced immune cell infiltration in various organs and helped alleviate organ damage, consequently improving survival rates in a rat sepsis model. This multitarget immunosorbents strategy offers significant advantages in design, efficiency, and biosafety, presenting a promising therapeutic approach for sepsis and other inflammatory diseases. STATEMENT OF SIGNIFICANCE: Sepsis remains lethal with limited treatments addressing both endotoxins and cytokines. We developed a multitarget nanobody-based immunosorbent (PS-Arg-Nb) that synergistically captures endotoxins (2211.77 EU/g) and cytokines (e.g., 92.10 % TNF-α removal) via arginine modification, nanobody recognition, and mesoporous adsorption. It demonstrates rapid clearance, improves survival by >40 % in septic rats, and exhibits excellent biocompatibility. This strategy offers a safe and efficient hemoperfusion solution for sepsis therapy.