Nebulized Inhalation of Engineered Extracellular Vesicles to Destruct Pre-metastatic Niche and Inhibit Postoperative Lung Metastasis in a Mouse Model.

Pre-metastatic niche (PMN) in the distant organs provides a suitable soil for the colonization of circulating tumor cells (CTCs). Targeting PMN destruction is becoming an effective strategy against tumor metastasis. Considering that the lung is the organ with the highest incidence of melanoma metastasis, nebulized inhalation can directly deliver drugs to the lung. Herein, M1 macrophage-derived, CXCR4-overexpressed, and BMS202-loaded extracellular vesicles (BMS@C-M1 EV) were constructed to inhibit postoperative melanoma lung metastasis. After nebulized inhalation, BMS@C-M1 EV effectively accumulated in the lungs of postoperative melanoma mice, its surface CXCR4 could inhibit the recruitment of monocytic myeloid-derived suppressor cells (mo-MDSCs) by consuming CXCL12, and its M1 pro-inflammatory feature repolarized tumor-associated macrophages (TAMs) from the M2 pro-tumor phenotype into the M1 antitumor phenotype, thereby reversing the immunosuppressive microenvironment, activating the T cell immune response, and preventing PMN construction. Furthermore, BMS202 released by BMS@C-M1 EV could induce the dimerization of PD-L1 in CTCs to block the PD-1/PD-L1 interaction, thereby enhancing T cell-mediated immune elimination of CTCs and further inhibiting the occurrence of metastasis. Therefore, BMS@C-M1 EV through nebulized inhalation could disrupt PMN formation and eliminate CTCs in the lung, effectively suppressing postoperative melanoma lung metastasis. This therapeutic approach holds great potential for preventing postoperative melanoma lung metastasis.