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.