Lung-retentive liposomes via monocyte recruitment for the treatment of acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory disease with a high mortality rate. Conventional in vivo monocyte-targeted strategies are fundamentally limited by the low physiological abundance of circulating monocytes, which represents a major unmet technical barrier on delivery efficiency. Herein, we report an organ-to-cell cascade-targeting strategy that overcomes this long-standing barrier via in situ monocyte recruitment in the pulmonary microvasculature. Herein, we engineered mMP-DDAB, a methylprednisolone (MPS)-loaded liposome co-modified with the lung-targeting functional lipid and CCR2-binding peptide. By virtue of DDAB-mediated lung retention and MP-triggered chemotaxis, mMP-DDAB first accumulates in the pulmonary microvasculature, then actively recruits monocytes, achieving an organ-to-cell cascade-targeting delivery. Following monocyte-targeted delivery and sustained MPS release, mMP-DDAB exerted potent anti-inflammatory and pro-resolving effects in the LPS-induced ARDS mouse model, as evidenced by reduced BALF neutrophil infiltration and protein leakage, suppressed pro-inflammatory cytokines, modulated the pulmonary monocyte/macrophage activation profile toward a more pro-resolving state, and mitigated histopathological lung injury.