Metabolic Tagging of Tumour Extracellular Vesicles for Targeted Modulation of Dendritic Cells

Extracellular vesicles (EVs) have emerged as a promising alternative to cell-based therapies due to their benign safety profiles and favourable pharmacokinetic properties. Tumour EVs, in particular, have shown promise to function as a therapeutic cancer vaccine for various cancer types. However, the efficient and targeted delivery of EVs to dendritic cells, the prominent type of antigen-presenting cells in the body, remains a challenge. Here we report the metabolic tagging of tumour EVs with azido groups for subsequent conjugation of anti-DEC205 via efficient click chemistry. We showed that azido-sugars can metabolically label cancer cells with azido groups and that azido-labelled cells can secrete azido-tagged EVs. Anti-DEC205, upon facile modification with dibenzocyclooctyne, was successfully conjugated onto azido-tagged EVs. Anti-DEC205-conjugated EVs were preferentially internalized by dendritic cells over other types of immune cells, and improved the processing and presentation of EV-encased antigens by dendritic cells. We further demonstrated the ability of anti-DEC205-conjugated EVs to induce enhanced cytotoxic T lymphocyte responses and antitumor efficacy in comparison with control EVs. Our study provides a facile and universal approach to chemically tagging EVs and conjugating targeting moieties to EVs, for targeted modulation of cells of interest.