Sepsis is a systemic inflammatory response syndrome (SIRS) characterized by massive secretion of pro-inflammatory cytokines and consequent multiple organ failure. Acute lung injury is a serious complication with high mortality caused by SIRS. Although many different antimicrobial and immunosuppressive therapies have been adopted to treat sepsis, its clinical management is still challenging due to the difficulty in correcting the persistent inflammation and immune imbalance. As an important component of the innate immune system, macrophages play a key role in the pathogenesis of many inflammatory diseases, such as sepsis. In the early stage of sepsis, activated macrophages exhibit hyperinflammation, causing tissue and organ injury. Restraining early excessive inflammatory response and late immunosuppression by controlling macrophage activity will be promising for sepsis treatment.
The team led by Professor Zhao Wei, from the College of Pharmacy, Nankai University, and the State Key Laboratory of Medicinal Chemical Biology, published a research paper titled “Combination Therapy with Resveratrol and Celastrol Using Folic Acid-functionalized Exosomes Enhances the Therapeutic Efficacy of Sepsis” in the international academic journal Advanced Healthcare Materials.
The complex inflammatory microenvironment in sepsis reveals multiple targets for specific and effective treatment. A major difficulty in moving the combination therapy forward is safely and effectively delivering medicine to the lesion site. Targeted delivery of therapeutic drugs to specific cells has been one of the greatest medical challenges, and many efforts have been made to modify delivery systems to enhance tissue biodistribution.
This study aims to use folic acid (FA)-functionalized exosomes (Exos) to enhance the strength of targeted delivery to M1 macrophages, increase drug accumulation in the disease site (lung), and reduce the on-target off-tumor effect. By further realizing the combined delivery of resveratrol (ESV) and celastrol (Cel) using FA-functionalized Exos (FA-Exo/R+C) through modern pharmaceutical technology, the synergistic resistance to excessive inflammatory response and immune imbalance in sepsis can be achieved. FA-functionalized Exo (FA-Exo) has been proven to be an excellent targeted drug delivery system, which enables Exos to be more localized to the lung and almost achieves co-localization of Exos with macrophages. FA-Exo/R+C exhibits powerful anti-inflammatory and immunosuppressive activities by regulating NF-κB and ERK1/2 signaling pathways, thereby reducing the levels of pro-inflammatory cytokines and the percentage of M1 macrophages. In the lipopolysaccharide-induced sepsis mouse model, FA-Exo/R+C significantly reduced the inflammatory cytokine storm and prevented acute lung injury and multiple organ dysfunction. More importantly, repeated administrations of FA-Exo/R+C evidently enhanced and prolonged the protective effect and resisted another hit by lipopolysaccharide, showing superior protective action in vivo and greatly improving the survival rate. These findings provide new strategies for curing sepsis and other inflammatory diseases.
Nankai University is the first completion unit of the research paper; Zheng Xue, a doctoral student of Nankai University, is the first author; Professor Zhao Wei, Dr. Jin Hongzhen of Nankai University, and researcher Yu Fan of University of Health and Rehabilitation Sciences are the co-corresponding authors. The research was funded by the National Key R&D Program and the National Natural Science Foundation of China.
