Exosomes Derived from Cancer Cells Relieve Inflammatory Bowel Disease in Mice

ABSTRACT

Exosome therapy has garnered significant attention due to its natural delivery capabilities, low toxicity, high biocompatibility, and potential for personalized treatment through engineering modifications. Recent studies have highlighted the ability of tumor cell-derived exosomes (TDEs) to interact with immune cells or modify the immune microenvironment to suppress host immune responses, as well as their unique homing ability to parental cells. The core question of this study is whether this immunomodulatory property of TDEs can be utilized for the immunotherapy of inflammatory diseases. In our experiments, we prepared exosomes derived from murine colon cancer cells CT26 (CT26 exo) using ultracentrifugation, characterized them, and conducted proteomic analysis. The therapeutic potential of CT26 exo was evaluated in our dextran sulfate sodium salt (DSS)-induced inflammatory bowel disease (IBD) mouse model. Compared to the control and 293T exo treatment groups, mice treated with CT26 exo showed a reduction in the disease activity index (DAI) and colon shortening rate, with no noticeable weight loss. Hematoxylin and eosin (H&E) staining of colon paraffin sections revealed reduced inflammatory infiltration and increased epithelial goblet cells in the colons of CT26 exo-treated group. Furthermore, we conducted preliminary mechanistic explorations by examining the phenotyping and function of CD4⁺ T cells and dendritic cells (DCs) in the colonic lamina propria of mice. The results indicated that the ameliorative effect of CT26 exosomes might be due to their inhibition of pro-inflammatory cytokine secretion by colonic DCs and selective suppression of Th17 cell differentiation in the colon. Additionally, CT26 exo exhibited good biosafety. Our findings propose a novel exosome-based therapeutic approach for IBD and suggest the potential application of TDEs in the treatment of inflammatory diseases.

Keywords:

• Immunotherapy
• Exosomes
• Inflammatory Bowel Disease
• IBD
• Tumor derived exosomes

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Notes on contributors

Shuyi Zhang

Shuyi Zhang received her B.S.degree (2020) from Naval Medical University. She is now pursuing a master’s degree under the direction of Prof. Shi Hu at Department of Biophysics, College of Basic Medical Sciences, Naval Medical University. Her current research direction aims at the therapeutic application of small extracellular vesicles in cancer.

Guangyao Li

Guangyao Li received his M.D.degree (2023) from Naval Medical University. He is currently a PhD student working under the direction of Prof. Shi Hu at Department of Biophysics, College of Basic Medical Sciences, Naval Medical University. His current research direction aims at antibody engineering and pathogen biology.

Kewen Qian

Kewen Qian received her B.S.degree (2021) from Naval Medical University. She is now pursuing a master’s degree under the direction of Prof. Shi Hu at Department of Biomedical Engineering, College of Basic Medical Sciences, Naval Medical University. Her current research primarily revolves around cellular immunotherapy and therapeutic application of small extracellular vesicles.

Yitan Zou

Yitan Zou received her B.S.degree (2018) from Naval Medical University and had worked as a physician in Changhai Hospital for 5 years. She is now pursuing a master’s degree under the direction of Prof. Shi Hu at Department of Biomedical Engineering, College of Basic Medical Sciences, Naval Medical University. Her current research mainly focuses the application of exosomes derived from mesenchymal stem cells in respiratory diseases.

Xinya Zheng

Xinya Zheng received her B.S. degree (2023) from Yangtze University. She is now pursuing a master's degree under the direction of Prof, Shi Hu at Department of Biomedical Engineering.College of Basic Medical Sciences, Naval Medical University. Her current research primarily revolves around treatment of inflammation by plant exosomes.

Hongru Ai

Hongru Ai received her B.S degree (2023) from the clinical medical college of Tianjin medical university. She is currently pursuing her master's degree in the Department of Medical Technology at University of Shanghai for Science and Technology under the supervision of Prof. Shi Hu. Her current research direction aims at antibody engineering.

Changhai Lei

Changhai Lei received his PhD degree from Second Military Medical University. He is currently a professor at Department of Biophysics, College of Basic Medical Sciences, Naval Medical University. His research interests include tumor biology and antibody‐based therapy.

Shi Hu

Shi Hu currently serves as an associate professor of biomedical engineering at Naval Medical University. His laboratory is mainly interested in engineered therapeutics, primarily development of novel therapeutic antibodies or cell‐based agents. In the last decade, he has focused on the development of novel therapeutics that underlie the mechanism of tumor heterogeneity and plasticity. He has authored over 40 scientific publications in peer‐reviewed journals and additional reviews and chapters in books on the molecular, biochemical, and cellular aspects of synthetic immunology and engineering.