Strain-specific magnetic nanoantidote with lipopolysaccharide recognition for systemic immune reprogramming in drug-resistant sepsis

Sepsis mortality is exacerbated by the endotoxin paradox, wherein conventional antibiotic-induced bacterial lysis triggers massive lipopolysaccharide (LPS) release, often culminating in an irreversible cytokine storm. Addressing the structural heterogeneity of the LPS O-antigen that hinders broad-spectrum neutralization, we report a magnetic nanoantidote (LPS-Zr-MIP@PS) engineered for precise extracorporeal blood purification. Utilizing metal-affinity-oriented surface imprinting technology, we established a dual-functional interface where Zr(IV) coordination pivots not only dictate the formation of highly ordered recognition cavities for strain-specific LPS capture but also synergistically amplify reactive oxygen species generation by ~14% under white-light irradiation. This integrated capture-kill-clearance nanoplatform demonstrated > 97.4% eradication efficiency against both wild-type and gentamicin-resistant Escherichia coli O55:B5. In a murine sepsis model, extracorporeal hemoperfusion treatment, targeting only 5% of the total blood volume daily, achieved an 80% survival rate and restored systemic hematological homeostasis. Multi-compartmental proteomics revealed molecular signatures across serum and vital organs that are consistent with attenuated TLR4/NF-κB signaling and enhanced endogenous antioxidant defenses, suggesting that the reduction in circulating pathogen-associated molecular patterns (PAMPs) and inflammatory mediators may contribute to alleviating the septic inflammatory cascade. This study provides a robust, clinically translatable strategy for the management of multidrug-resistant sepsis and other endotoxin-driven pathological conditions, bridging the gap between advanced interface engineering and clinical hemoperfusion practice.