Inhalable PD‐1 Exosomes Co‐Delivering EP2/EP4 Antagonists Remodel the Pulmonary Tumor Microenvironment in Breast Cancer Lung Colonization

Developing effective nanomedicines for pulmonary metastasis remains challenging because of systemic clearance and local stromal barriers. Guided by single-cell transcriptomic profiling, we characterized a compartmentalized immunosuppressive network involving PGE2 and provide a biological rationale for coordinated EP2/EP4 antagonism. We therefore engineered an inhalable biomimetic platform (PD-1@E2/4 Exo) comprising PD-1-displaying exosomes co-loaded with EP2 and EP4 antagonists. Compared with intravenous administration, nebulized delivery increased pulmonary exposure of the engineered vesicles. Within the pulmonary tumor setting, surface PD-1 is intended to interfere with PD-1/PD-L1 signaling, while the co-delivered antagonists target the EP2/EP4 immunosuppressive axis. Treatment was associated with macrophage reprogramming, increased oxidative stress, and enhanced ICD-related responses in tumor cells. In the experimental breast-cancer lung-colonization model, the inhaled formulation reduced established pulmonary tumor burden and was accompanied by systemic immune-memory responses. These findings provide a preclinical study for integrating local pulmonary delivery with coordinated metabolic and immune modulation in breast cancer lung disease.