Bioengineered Neutrophil Extinguisher Targets Cascade Immune Pathways of Macrophages for Alleviating Cytokine Storm in Pneumonia

Abstract

Cytokine storm is a common complication of COVID-19 pneumonia and has been proven to contribute to high mortality rates. However, current treatment approaches exhibit limited potential to balance immune response and overproduction of inflammatory cytokines, leading to poor therapeutic outcomes. Herein, a smart bioengineered neutrophil, Extinguisher, composed of live neutrophils encapsulating the liposome formulation of NF-κB suppressor MLN4924 and STING inhibitor H-151 (Lip@MH), is developed for alleviating the hyperinflammatory cytokine storm. Extinguisher inherits motility and chemotaxis characteristics of neutrophils, allowing for the specific delivery and sustained release of Lip@MH within inflamed tissues. Subsequently, Lip@ MH effectively transports anti-inflammatory agents into macrophages and synergistically inhibits inflammatory pathways of NF-κB and STING, leading to decreased production of cytokines. In vivo studies demonstrate that Extinguisher not only selectively accumulates at the site of pneumonia caused by Pseudomonas aeruginosa-induced acute lung injury but inhibits the production of inflammatory factors through regulating NF-κB/STING signaling pathways, thereby effectively calming cytokine storm. Importantly, Extinguisher significantly improves therapeutic benefits and survival in mice with acute pneumonia. Therefore, Extinguisher represents an appropriate combination of cell therapy and immunoregulation for cytokine storm intervention and may bring insights into the treatment of COVID-19 pneumonia.

Nanotechnology’s frontier in combatting infectious and inflammatory diseases: prevention and treatment

“…82 – 84 Also, some studies have found that liposomes can neutralize inflammation or regulate and mitigate the cytokine storm against infections and their resulting inflammatory responses. 85 With the action of liposomes, anti-inflammatory drugs were transported to macrophages, inhibiting signaling pathways involved in inflammation and thereby calming the cytokine storm. 86 However, some studies have reported that drug-loaded liposomes can induce inflammatory responses during infection.…”

The Role of the Nuclear Factor-Kappa B (NF-κB) Pathway in SARS-CoV-2 Infection

“…Once at the target site, it releases Lip@MH, facilitating the transport of anti-inflammatory agents into macrophages. The dual action effectively inhibits NF-κB and STING-mediated inflammatory pathways, leading to a notable reduction in cytokine production [ 163 ]. Remarkably, in animal studies, extinguishers demonstrated selective accumulation at the pneumonia site and tangible mitigation of the cytokine storm through regulating NF-κB/STING signaling pathways, ultimately resulting in improved therapeutic outcomes [ 163 ].…”