Sugar-eaten bacteria could be controlled production of antitumor vaccines as a form of membrane vesicles at the gut of tumor bearing animals

In a study published in Nature Biomedical Engineering, a research team led by Prof. NIE Guangjun and Prof. ZHAO Xiao at National Center for Nanoscience and Technology (NCNST) of the Chinese Academy of Sciences, demonstrate that orally administered bacteria can be an effective vaccine carrier to secrete small membrane vesicles as the tumor vaccine at the gut to fight against various tumors of the animal models.

Compared with vaccination, oral vaccine is much easier to take, and mostly in a lower cost; and more importantly, it activates the body’s adaptive immune response by stimulating the immune cells in the intestine which is the largest immune organ. Therefore, it is expected to generate strong immune responses. However, the oral vaccine system is still very limited. There are two major challenges for the development of oral tumor vaccine. One is the harsh environment in digestive tract and the other is the complex intestinal epithelial barriers.

To overcome these challenges, the researchers developed an oral sugar-controlled bacteria robot to produce tumor vaccine in the gut. They designed a bacteria robot based on the genetically engineered E. coli which can secrete outer membrane vesicles (OMVs) carrying tumor antigens under the induction of arabinose, a five-carbon sugar that is found widely in nature.

As a natural mediator for interaction between the gut microbiota and the body’s immune system, OMVs together with tumor antigens can effectively penetrate the intestinal mucus and epithelial barrier, and be taken up by antigen-presenting cells in lamina propria, one special layer of mucosa of the gut. Ultimately, the oral vaccine system activates strong antitumor immune responses and immune memory effects in multiple preclinical tumor models.

“Initially, a report of bacterial enteritis by food contamination came to our attention. If pathogenic bacteria can break through biological barriers and provoke an immune response, artificial engineered bacteria should be able to overcome the complex gastrointestinal environment. Inspired by this hypothesis, we started to try to use bacterial robots to deliver oral vaccines” said Prof. ZHAO. “However, bacteria are too large to penetrate the thick mucus layer and intestinal epithelial barrier to reach the immune cells at lamina propria. Fortunately, numerous studies have demonstrated that OMVs released by intestinal bacteria are involved in the immune regulation of the body.”

“This work shows that this oral bacteria robot can controllably produce vaccines against multiple tumors in mice with the help of genetic engineering technology. What’s more, it can be used as an antigen delivery and display platform to prevent other disease, such as contagion, it holds great promise for further development of oral vaccines” said Prof. NIE.

The team established an oral vaccine system based on gut-controlled production of effector OMVs by genetically engineered bacteria. This oral vaccine system can efficiently activate the innate and adaptive immune responses, and may be further developed for treatment of various diseases.

YUE Yale, XU Jiaqi and LI Yao are the first authors of the current work. The research was funded by the National Key R&D Program of China, the Strategic Priority Research Program of the CAS, the CAS Project for Young Scientists in Basic Research and the National Natural Science Foundation of China.

Schematic diagram of the oral tumor vaccine based on bacterial robots(Image by NIE Guangjun et al)

Contact: NIE Guangjun

National Center for Nanoscience and Technology (NCNST)

E-mail: niegj@nanoctr.cn