Chloroquine-induced exosomal hybrid liposomes enable neutralization of endotoxins and exotoxins

Sepsis remains a major challenge in global clinical practice due to its persistently high mortality rate. Traditional antibiotics address symptoms rather than root causes, while the problem of drug resistance continues to escalate. Detoxification strategies such as monoclonal antibodies have shown limited efficacy in complex clinical settings, as their single-target specificity and narrow activity spectrum restrict their ability to neutralize diverse bacterial toxins. The therapeutic bottleneck lies in the absence of effective methods capable of simultaneously neutralizing Gram-negative bacterial endotoxins (such as LPS) and Gram-positive bacterial exotoxins (such as Hlα). To overcome this limitation, we drew inspiration from the natural "bait" mechanisms of living organisms to develop a biomimetic nanoscale detoxifier with broad-spectrum toxin adsorption and neutralization capacity. Specifically, chloroquine was used to inhibit autophagy lysosome formation in macrophages, promoting the release of exosomes enriched with toxin receptors CD14 and ADAM10. These exosomes (Exo) were then fused with artificial liposomes (Lip) possessing extensive membrane space to construct exosome membrane hybrid liposomes (Elip). Our results demonstrated that Elip effectively neutralized the hemolytic activity of Hlα and adsorbed LPS in vitro. In a subcutaneous HIα-induced local inflammation model, Elip completely prevented local skin and muscle tissue necrosis. In a systemic inflammation model induced by intravenous HIα, Elip significantly alleviated acute inflammatory damage in the lungs and liver, reducing key pro-inflammatory factor levels to near-normal ranges. In an LPS-induced shock model, all mice in the Elip treatment group survived. This study robustly confirmed that Elip successfully resolves the clinical challenge of simultaneously clearing endotoxins and exotoxins through a "synergistic detoxification" mechanism, offering a novel therapeutic strategy with significant translational potential that transcends traditional antibiotics for conquering sepsis.