Acute lung injury and idiopathic pulmonary fibrosis are severe lung diseases causing irreversible lung damage with a high mortality rate and ineffective treatment approaches. Excessive inflammatory response, abnormal self-repair, and fibrosis development are critical features in both pathologies. Macrophages are demonstrated to be critical in the initiation and progression of lung pathologies, driving inflammatory response, as well as irreversible injuries, such as fibrosis. Macrophages are cells with multiple functions regulated by various mediators, such as cytokines, metabolites, proteins, and miRNA carried in extracellular vesicles, also designated secretome. Hence, besides engulfing pathogens, these cells modulate the development and tissue homeostasis, remodeling, and repair, from embryonic to adult life effects, namely in the lung. During late fetal lung development, tissue macrophages hold a lung-specific transcriptional profile determinant to normal lung formation. We aim to elucidate whether macrophages’ genetic reprogrammed to molecules belonging to the unique macrophage fetal lung-specific transcriptional profile boost immature lung differentiation and injured lung regeneration. With this, we foresaw identify potential cell-free based therapies for prematurity and acute and chronic lung diseases.