Exosome-mediated macrophage polarization in pulmonary diseases: heterogeneity, signaling crosstalk, and translational challenges

Although exosomes and macrophages have been studied in lung diseases, an integrated framework linking exosomal cargo, macrophage heterogeneity, disease stage, and translational barriers is still lacking. Pulmonary diseases cause substantial morbidity and mortality, and the pulmonary immune microenvironment is shaped by complex cell–cell communication. Lung macrophages are key innate immune cells that display a spectrum of activation states, including M1-like, M2-like, and intermediate phenotypes. This review provides an integrated framework linking exosomal cargo, lung macrophage heterogeneity, signaling crosstalk, disease stage, and translational barriers. We summarize exosome biogenesis and lung macrophage ontogeny, focusing on how exosomes regulate macrophage polarization through NF-κB, PI3K/AKT, JAK/STAT, and ERK pathways and their crosstalk. We then discuss context-dependent effects in lung injury, COPD, asthma, pulmonary fibrosis, and lung cancer. We also review exosome engineering strategies for targeted macrophage modulation. Despite advances, clinical translation is limited by large-scale purification, targeted delivery, safety, and standardized quality control. We conclude that exosome-mediated macrophage regulation is context-dependent and promising, but translation requires MISEV-compliant exosome terminology, rigorous evidence grading, scalable manufacturing, and safe targeted delivery.