Biomimetic Immunosuppressive Exosomes that Inhibit Cytokine Storms Contribute to the Alleviation of Sepsis

Abstract

Sepsis is a disease characterized by multiple organ failure caused by immune hyperactivation and cytokine storms. Studies have shown that the incidence of sepsis in melanoma patients is substantially lower compared to the general population. It is also observed that experimental tumor‐bearing animals have high survival rates after sepsis induction, suggesting that tumors may suppress sepsis‐associated immune overactivation, thereby alleviating sepsis. Based on the above‐described findings, this work assesses whether tumor cells play an antisepsis role in mice through the secretion of exosomes. Analysis of exosome activity reveals that the induced exosomes (iExo) secreted by tumor cells following lipopolysaccharide (LPS) treatment improve sepsis to a greater extent than normal secretory exosomes. Further analysis reveals that iExo exert their protective effects mainly through seven key miRNAs. In vitro bionic simulation of exosomes is carried out using exosome mimics generated by loading the aforementioned microRNAs into hyaluronic acid–polyethylenimine nanoparticles. Exosome mimics at specific miRNA ratios alleviate sepsis in mice and cynomolgus monkeys, indicating that biomimetic simulation of tumor‐suppressive exosomes may represent a promising therapeutic method for the treatment of sepsis and cytokine‐storm‐related conditions.

Hybrid Biomimetic Nanovesicles to Drive High Lung Biodistribution and Prevent Cytokine Storm for ARDS Treatment

“…In order to examine the cellular membrane protein orientation on NVs and LNVs, immunolabeling with antibodies probed against their extracellular domain was designed (Figure S13A). CD44 and CD45 are glycoproteins with high expression on the cellular surface . Herein, PE-labeled anti-CD44 and PerCP-Cy5.5-labeled anti-CD45 antibodies were applied to bind the corresponding extracellular domain through surface staining and examined by flow cytometry (FCM).…”

“…32 CD44 and CD45 are glycoproteins with high expression on the cellular surface. 36 Herein, PE-labeled anti-CD44 and PerCP-Cy5.5labeled anti-CD45 antibodies were applied to bind the corresponding extracellular domain through surface staining and examined by flow cytometry (FCM). Both CD44 and CD45 were detected, showing a positive ratio of ∼70%, which suggested the presence of these membrane proteins on the surface of NVs and LNVs.…”

Nanosystems for Immune Regulation against Bacterial Infections: A Review

“…Sepsis is a life-threatening disease caused by microbial infection-induced immune hyperactivation and cytokine storms. Inspired by the fact that melanoma patients have a low incidence of sepsis and experimental tumor-bearing animals have high survival rates after sepsis induction, Li and co-workers found that induced exosomes (iExo) secreted from LPS-treated cancer cells could alleviate sepsis effectively compared to normal exosomes (nExo) . Then, the antisepsis mechanism of iExo was investigated.…”

“…Inspired by the fact that melanoma patients have a low incidence of sepsis and experimental tumor-bearing animals have high survival rates after sepsis induction, Li and co-workers found that induced exosomes (iExo) secreted from LPS-treated cancer cells could alleviate sepsis effectively compared to normal exosomes (nExo). 66 Then, the antisepsis mechanism of iExo was investigated. iExo could inhibit the expression of TLR4, myeloid differentiation primary-response protein 88 (MyD88), and NF-κB, impede LPS-induced macrophage M1 polarization and promote M2 polarization, and downregulate the levels of adhesion molecules (such as ICAM-1 and chemokine MCP-1) in endothelial cells.…”

The Impact of Curcumin on Immune Response: An Immunomodulatory Strategy to Treat Sepsis

“…Sepsis is, thus, a situation where there is a pronounced stimulation of innate immunity along with the inhibition of the conventional T-cell-originated immune response and with an increase in regulatory T cells (Tregs). This, then, provokes the onset of a sepsis-correlated immunosuppression [ 39 , 40 , 41 ] and leads to a disturbance of the immune response and possible subsequent organ damage [ 42 , 43 ].…”