Metabolic tagging of extracellular vesicles and development of enhanced extracellular vesicle based cancer vaccines

As key mediators of cellular communication, extracellular vesicles (EVs) have been actively explored for diagnostic and therapeutic applications. However, effective methods to functionalize EVs and modulate the interaction between EVs and recipient cells are still lacking. Researchers at the University of Illinois at Urbana-Champaign have developed a facile and universal metabolic tagging technology that can install unique chemical tags (e.g., azido groups) onto EVs. The surface chemical tags enable conjugation of molecules via efficient click chemistry, for the tracking and targeted modulation of EVs. In the context of tumor EV vaccines, the researchers show that the conjugation of toll-like receptor 9 agonists onto EVs enables timely activation of dendritic cells and generation of superior antitumor CD8+ T cell response. These lead to 80% tumor-free survival against E.G7 lymphoma and 33% tumor-free survival against B16F10 melanoma. This study yields a universal technology to generate chemically tagged EVs from parent cells, modulate EV-cell interactions, and develop potent EV vaccines.

Metabolic tagging and targeting of EVs
and its use for the development of next-generation EV vaccines

Fig. 1

a Cells can be metabolically labeled with chemical tags (e.g., azido groups) via metabolic glycoengineering processes of unnatural sugars, for subsequent secretion of azido-tagged EVs. The azido-labeled EVs can then mediate conjugation of DBCO-cargo via efficient and bioorthogonal click chemistry, for in vitro and in vivo tracking and targeting of EVs. b Development of next-generation EV vaccines by orchestrating the interaction between EVs and dendritic cells (DCs). Cells (e.g., tumor cells) from patients can be metabolically labeled to secrete azido-tagged EVs, for subsequent conjugation of TLR9 agonists via click chemistry. Upon in vivo administration, TLR9 agonist-conjugated EVs can be internalized by DCs via endosomes where TLR9 is present. The binding of TLR9 agonist on the surface of EVs to TLR9 on endosomes can stimulate DCs in a timely manner, leading to improved processing and presentation of EV-encased antigens. As a result, enhanced CTL response and antitumor efficacy can be achieved.

Bhatta R, Han J, Liu Y, Bo Y, Lee D, Zhou J, Wang Y, Nelson ER, Chen Q, Zhang XS, Hassaneen W, Wang H. (2023) Metabolic tagging of extracellular vesicles and development of enhanced extracellular vesicle based cancer vaccines. Nat Commun 14(1):8047. [article]

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