Cytokine nanosponges suppressing overactive macrophages and dampening systematic cytokine storm for the treatment of hemophagocytic lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a highly fatal condition with the positive feedback loop between continued immune cell activation and cytokine storm as the core mechanism to mediate multiple organ dysfunction. Inspired by macrophage membranes harbor the receptors with special high affinity for proinflammation cytokines, lipopolysaccharide (LPS)-stimulated macrophage membrane-coated nanoparticles (LMNP) were developed to show strong sponge ability to both IFN-γ and IL-6 and suppressed overactivation of macrophages by inhibiting JAK/STAT signaling pathway both in vitro and in vivo. Besides, LMNP also efficiently alleviated HLH-related symptoms including cytopenia, hepatosplenomegaly and hepatorenal dysfunction and save the life of mouse models. Furthermore, its sponge effect also worked well for five human HLH samples in vitro. Altogether, it's firstly demonstrated that biocompatible LMNP could dampen HLH with high potential for clinical transformation, which also provided alternative insights for the treatment of other cytokine storm-mediated pathologic conditions such as COVID-19 infection and cytokine releasing syndrome during CAR-T therapy.

Graphical abstract

Highlights

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  LMNP functioned better as a multiple-cytokine sponging tool when compared with conventional macrophage coated nanoparticles.

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  LMNP sponged inflammation cytokines and suppressed macrophage overactivation by inhibiting JAK/STAT signaling pathway.

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  LMNP calmed down systematic cytokine storm and dampened HLH in HLH mice models.

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  LMNP also worked well in sponging cytokines in human HLH samples which indicated high potential of clinical transformation.