Cyclic Strain and Macrophage-Mediated Transport Govern Micron-Sized PM2.5 Translocation across the Air–Blood Barrier

PM 2 . 5 translocated across the air-blood barrier (ABB) can accumulate in the lungs and extrapulmonary organs, leading to both pulmonary and systemic pathophysiological effects. However, the mechanisms governing the translocation of micron-sized PM 2 . 5 (MPs) remain unclear. Here, a physiologically relevant in vitro ABB model is developed, comprising a triple co-culture system under respiratory-like cyclic strain. Using this platform, it is demonstrated that cyclic stretching enhances dTHP-1 phagocytosis and transmigration, synergistically promoting macrophage-mediated MPs translocation across the ABB in combination with strain-induced disruption of epithelial tight junctions. This cooperative mechanism governs MPs translocation across the ABB and markedly increases the transport of 2 µm particles compared to static conditions. By using scavenger receptor A (SR-A) inhibitors, this process are confirmed to be predominantly driven by macrophage phagocytosis. Furthermore, this study explores the potential fate of particles post-translocation, proposing their subsequent release from macrophages via active lysosomal exocytosis and passive release mediated by cell death. These findings provide new insights into mitigating PM 2 . 5 -induced health risks and inform macrophage-assisted pulmonary drug delivery strategies.