Spatiotemporally stratified nanoassemblies for precisely halting the immunothrombotic vicious cycle in acute lung inflammation

Acute lung injury and acute respiratory distress syndrome have high mortality. Extensive pulmonary microvascular thrombosis occurs in over 80% of patients who die from severe pneumonia. Inflammation and thrombosis mutually aggravate each other, forming a vicious cycle that accelerates disease progression. Nevertheless, it remains challenging to achieve safe and balanced anti-inflammatory treatment and systemic anticoagulation. These two pathological processes are spatially separated, coagulation arises on the vascular endothelial surface, while inflammatory signals are confined inside immune cells. Current therapeutic strategies fail to realize simultaneous and precise dual regulation within a single delivery system. Therefore, we developed a spatiotemporally hierarchical responsive nanoplatform called Hep-PBA/Dex@TAF. The outer Hep-PBA layer accumulates at the lesion sites by targeting P-selectin on the inflamed pulmonary endothelium. In the weakly acidic local microenvironment, boronate-ester bonds break, releasing Hep-PBA for local anticoagulation. The exposed Dex@TAF core is internalized by macrophages through the recognition between tannic acid and toll-like receptor 4. Subsequently, intracellular metal-polyphenol networks are disassembled. Relying on the proton sponge effect, dexamethasone escapes from lysosomes and is released into the cytoplasm, whereas reactive oxygen species are eliminated via the Fe²⁺/Fe³⁺ redox cycle. The released dexamethasone activates glucocorticoid receptors and suppresses proinflammatory transcription, further reducing neutrophil activation and neutrophil extracellular trap production. This synergistic regulation blocks the inflammation-thrombosis cascade by alleviating platelet activation and endothelial injury. In a mouse model of acute lung injury complicated by thrombosis, this nanoplatform markedly alleviated cytokine storms, preserved the integrity of the lung tissue structure, and inhibited microthrombus formation. In conclusion, Hep-PBA/Dex@TAF serves as a precise and dual-functional intervention strategy for comorbid inflammation and thrombosis.