Functional Modification of Probiotic-Derived Extracellular Vesicles Based on Bioorthogonal Reaction for Immunotherapy: Hydrogelation and Immunoactivities

Abstract

Cells are involved in various biological events by transporting message substances such as proteins and nucleic acids to target cells. Recently, it was revealed that extracellular vesicles (EVs), which are cell-secreted membrane particles, function as intercellular delivery vehicles. As EVs reflect the characteristics of their parent cells, the development of novel EV-based therapies is expected. Moreover, it has become clear that microorganisms also secrete EVs. Probiotics are live microorganisms that confer a health benefit on the host and known to secret EVs. However, the information about the characteristics of probiotic-derived EVs is not fully understood. Furthermore, there were no technologies to modify the functionality of probiotic-derived EVs, such as formulation and drug loading, which are essential for their practical application. Therefore, we aimed at elucidation of the usefulness of probiotic-derived EVs and development of technologies for their functionalization. First, as an evaluation of the usefulness of probiotic-derived EVs, we evaluated the effects on the innate immune response, which is the initial immune response of the host. Next, we elucidated the pharmacokinetics and immunostimulatory effects of EVs when administered to the mice. Furthermore, we developed a novel functional modification technology of EVs by combining the amino acid metabolism mechanism and the bio-orthogonal reaction, aiming at the application of probiotic-derived EVs to immunotherapy. These findings will be helpful for the development of immunotherapy based on probiotic-derived EVs with superior safety and efficacy.