Targeting pre-metastatic niche with inhalable dendritic cell vesicles to prevent breast cancer lung metastasis.

Distant metastasis remains the primary cause of mortality in breast cancer, yet therapeutic options to prevent or treat metastatic progression are still limited. Emerging evidence suggests that the formation of the pre-metastatic niche (PMN) serves as a pivotal step in the process of breast cancer metastasis. Lung tissue is the major site of breast cancer metastasis with elevated prostaglandin E2 (PGE(2)) levels, which fosters immunosuppression and promotes niche establishment. Although EP2 and EP4 receptor antagonists have shown promise in counteracting PGE(2)-driven immunosuppression, their clinical translation is hindered by poor selectivity and bioavailability. To address these limitations, we developed a nanotherapeutic platform using dendritic cell-derived nanovesicles (NVs) engineered with α-lactalbumin (α-LA) and loaded with the EP2 antagonist TG6-10-1 and the EP4 antagonist GW627368, termed L-TG/GW-NVs. L-TG/GW-NVs exploit the homing ability of DC-derived NVs and retain immune-stimulatory molecules, thereby preventing PMN formation by blocking PGE(2) signaling and reactivating suppressed dendritic cells and cytotoxic T cells. This synergistic strategy markedly suppressed lung metastasis by disrupting niche formation, enhancing immune activation, and reversing T cell exhaustion. Collectively, our findings establish a novel framework for metastatic breast cancer therapy and provide valuable insights for future translational studies and combinational immunotherapies.