Tri-specific molecularly imprinted lysosomal nanodegrader enables synergistic therapy of cytokine storm

The excessive release of proinflammatory cytokines, especially IL-6 and TNF-α, plays a critical role in the pathogenesis of cytokine release syndrome, also known as a cytokine storm. Although targeted cytokine degradation holds great promise in controlling the overwhelming inflammation, its development for early intervention in cytokine storm is impeded by several challenges, including limited modularity, high preparation cost, complex synthetic procedures, and a limited number of substrates amenable to degradation. Herein, we developed a tri-specific molecularly imprinted polymer (tsMIP)-based lysosome-targeted chimera for simultaneous targeted degradation of IL-6 and TNF-α towards synergistic anti-inflammatory therapy of cytokine storm. The tsMIP was synthesized using N- or C-terminal nonapeptide epitopes of IGF2R, IL-6 and TNF-α as the templates, enabling high-affinity binding to all three proteins. Following rational administration during cytokine storm, tsMIP first captured the cytokines IL-6 and TNF-α, then targeted IGF2R on the cell surface, and finally transported the cytokines into lysosomes for degradation. This treatment significantly reduced the levels of the pro-inflammatory cytokines and the downstream phosphorylated STAT3/NF-κB p65 proteins as well, indicating effective lysosomal degradation and downstream signaling pathway blockade. <i>In vivo</i> verification in an acute lung injury mouse model, as a typical example of cytokine releasing syndrome, demonstrated potent inflammation mitigation of intranasal tsMIP administration. As a proof-of-concept, this study highlights the potential of a tri-specific molecularly imprinted lysosomal nanodegrader in achieving synergistic anti-inflammation effects, offering a versatile strategy for treating cytokine storm and other infectious and inflammatory diseases.