Tumor-derived exosomes can specifically prevent cancer metastatic organotropism

Each type of cancer has its own specific metastatic route developed by disseminating circulating tumor cells (CTCs) and related extracellular vesicles to the target organ, i.e., metastasis organotropism. Tumor-derived small extracellular vesicles (herein exosomes, EXO) play an important role in determining cancer organotropic metastases to pre-metastasis niches. We therefore hypothesized that drug-loaded EXO may mix well with their companion small extracellular vesicles to specifically target the aimed metastatic organ via organotropism. Here, we demonstrate that the circulating breast-cancer-derived EXO loaded with doxorubicin (EXO-DOX) can mingled with their original companion EXO and inhibit breast cancer metastasis to lungs. The CD47 on the EXO-DOX prevented EXO-DOX from immune attack and prolonged their circulation in blood. The tissue distribution ratio of EXO-DOX is identical to the ratio of their companion EXO due to the specific affinity of EXO to integrins in targeted tissues. Quantitative accumulation of EXO-DOX in the mouse lungs is proportional to the organotropism of the circulating breast cancer cells that disseminate from subcutaneously-implanted human breast cancer cells in mice. EXO-DOX inhibited angiogenesis and cancer cell proliferation, resulting in prevention of breast cancer metastasis to the lungs. This study opens a novel path to use Trojan small extracellular vesicles for specifically controlled release of active components by small extracellular vesicles organotropism mechanism to the targeted organ for disease chemoprevention.