T-Cell-Derived Extracellular Vesicles with an Antitransferrin Receptor Antibody for Multicancer Targeting.

Abstract

Recent research has explored the anticancer properties of immune-cell-derived small extracellular vesicles (sEVs), but many challenges, like the need for improved targeting, remain. To address these challenges, we engineered T-cell-derived sEVs with antitransferrin receptor 1 (TfR1) antibodies (T-EVs). This modification enhanced the delivery of sEV to six types of cancer cells, as confirmed by flow cytometry, immunocytochemistry, live cell imaging, and blocking experiments <i>in vitro</i>. The T-EVs also reduced PD-L1 and Rab27a levels, decreased sEV production from breast cancer cells, and increased susceptibility to CD8⁺ T-cell-mediated cytotoxicity. Systemically administered T-EVs efficiently targeted breast, lung, and skin tumors in mouse models. Notably, T-EVs significantly inhibited tumor growth without systemic toxicity. Additionally, T-EVs reduced PD-L1 and Rab27a levels in cancer cells while enhancing the CD8⁺ T-cell cytotoxicity and proliferation. Overall, this study highlights the anticancer effects of T-EVs against multiple cancer types, underscoring their potential in developing targeted cancer therapies.