A living neutrophil Biorobot synergistically blocks multifaceted inflammatory pathways in macrophages to effectively neutralize cytokine storm.

Cytokine storm is a potentially life-threatening immune response typically correlated with lung injury, particularly in people with underlying disease states, such as pneumonia. Therefore, the prompt treatment of cytokine storm is essential for successful recovery from a potentially fatal condition. Herein, a living anti-inflammatory Biorobot (firefighter), composed of neutrophils encapsulating mannose-decorated liposomes of the NF-κB inhibitor TPCA-1 and STING inhibitor H-151 (M-Lip@TH, inflammatory retardant), is developed for alleviating hyperinflammatory cytokine storm through targeting multiple inflammatory pathways in macrophages. Biorobot fully inherits the chemotaxis characteristics of neutrophils, and efficiently delivers and releases therapeutic M-Lip@TH at the inflammatory site. Subsequently, M-Lip@TH selectively targets macrophages and simultaneously blocks the transcription factor NF-κB pathway and STING pathway, thereby preventing the overproduction of cytokines. Animal studies show that Biorobot selectively targets LPS-induced acute lung injury, and not only inhibits the NF-κB pathway to suppress the release of various pro-inflammatory cytokines and chemokines, but also blocks the STING pathway to prevent an overactive immune response, which helps to neutralize cytokine storms. Particularly, Biorobot reduces lung inflammation and injury, improves lung function, and increases the survival rates of pneumonia mice. Therefore, Biorobot represents a rational combination therapy against cytokine storm, and may provide insights into the treatment of diseases involving overactive immune responses.