Abstract

The capacity of host professional phagocytes to attenuate excessive inflammatory responses through pathogen cloaking during infection has been well‐established. However, the involvement of non‐professional phagocytes in this process remains unknown. Here, we identify a previously unrecognized mechanism by which lung epithelial cells (LECs) attenuate inflammatory responses during Staphylococcus aureus infection. S. aureus ‐challenged LECs rapidly shed extracellular vesicles (EVs) carrying surface receptors capable of binding invading bacteria and forming EV‐bacteria complexes. The EV‐bacteria complexes were internalized by LECs via RhoA‐ROCK1‐actin‐driven endocytosis pathway, reducing free bacterial burden within the alveolar lumen. This EV‐mediated pathogen cloaking conferred acute‐phase protection, as demonstrated by mitigating early‐stage pulmonary inflammation, and improving survival rates in infected mice. Paradoxically, this strategy permitted chronic bacterial persistence and sustaining low‐grade inflammation. Our findings delineate a trade‐off mechanism that non‐professional phagocytes modulate acute bacterial infection and inflammatory responses via pathogen cloaking. This mechanistic perspective reframes non‐professional phagocytes as active architects of infection outcomes based on EV‐mediated host‐pathogen interactions. Our work provides insights into the mechanism of bacterial cloaking during infection and suggests stage‐specific therapeutic strategies. Schematic diagram of lung epithelial cell‐derived extracellular vesicles mediating bacterial cloaking to attenuate acute inflammatory injury. Lung epithelial cells attenuate early S. aureus infection by shedding extracellular vesicles that capture bacteria via surface receptors. These EV‐bacteria complexes are internalized through a RhoA‐ROCK1‐actin pathway, reducing acute inflammation but enabling chronic persistence. This study delineates a trade‐off cloaking mechanism for non‐professional phagocy