Lipo-protein deposition strategy towards smart microspheres with bacterial toxin triggered "adsorption-pore formation-immune regulation" cascade reaction for sepsis treatment.

Abstract

Sepsis induced by Gram-positive bacteria causes immune disorder and multi-organ damage driven by pore-forming toxins (PFTs), which directly form pores on host cell membrane and exacerbate cell damage. Traditional drug therapy cannot remove the existing bacterial toxins, and exacerbate inflammatory storm by increasing toxin release during bacterial lysis. Meanwhile, current materials for toxin clearance lack the capability to regulate the microenvironment and pose systemic retention risks. This study proposes smart microspheres with bacterial toxin triggered "adsorption-pore formation-immune regulation" cascade reaction. The liposomes with high affinity for α-toxin (K_D = 5.355 × 10^-8 M) are immobilized onto polyether sulfone (PES) microspheres through a "lipo-protein deposition" strategy to prepare PES-L-Lipo-RL microspheres for extracorporeal hemoperfusion. Toxin adsorption triggers drug release by the forming pores in liposomes, inhibiting bacterial proliferation and regulating immune microenvironment (CD86-positive macrophages reduce from 23.9% to 7.6%). Notably, the expressions of virulence genes (hla, agrA) are downregulated, reducing toxin production at the source. In a rabbit sepsis model, PES-L-Lipo-RL microspheres reduce bacterial load (antibacterial rate achieves over 99% within 1 h), alleviate cytokines release, avoid multi-organ damage, and remarkably increase 28-day survival rate to 100%. The smart cascade reaction integrating toxin adsorption and immune regulation provides an effective and safe approach for sepsis therapy.