Tumor-derived nanovesicles have been widely used as a
biomarker or therapeutic target in various
tumor types. However, these nanovesicles have limited use in
therapy due to the risk of advancing
tumor development. Methods: Exosome-like nanovesicles (ENVs) were developed from metastatic
breast cancer 4T1 cells-derived exosomes. The distribution of ENVs and their impact on macrophage-mediated phagocytosis were evaluated. The effect of ENVs pretreatment on anti-lung
metastasis therapeutic effects of chemotherapeutic drugs delivered by
DOTAP/DOPE
liposomes in
breast cancer-bearing mice was also examined. Results: We demonstrated that, following
intravenous injection in mice, ENVs were preferentially uptaken by Kupffer cells and repressed phagocytosis. The decreased uptake appeared to be due to the translocation of membrane
nucleolin from the inner face of the plasma membrane to the cell surface and intercellular Ca2+ fluxes, leading to altered expression of genes involved in phagocytosis by macrophages. Mice pretreated with 4T1-derived ENVs led to the decreased uptake of
DOTAP: DOPE
liposomes (DDL) in the liver. Consequently,
doxorubicin-loaded DDL transported to the lungs instead of the liver, effectively inhibiting
breast cancer lung
metastasis. Importantly, 4T1 cells exosome-derived ENVs had no detectable toxicity in vivo and low-risk to promote
tumor growth and
metastasis compared to 4T1 cells exosomes. Conclusion: Our results suggested that pretreatment with 4T1 ENVs represents a strategy to escape Kupffer cell-mediated phagocytosis effectively targeting drug delivery vehicles to
tumor metastasis, reducing the IC50 of the chemotherapeutic drugs, and avoiding adverse side effects.