Spatiotemporally stratified nanoassemblies for precisely halting the immunothrombotic vicious cycle in acute lung inflammation
- 1School of Pharmaceutical Science, Liaoning University, Shenyang 110036, China; Liaoning Key Laboratory of New Drug Research & Development, Liaoning University, Shenyang, 110036, China; Corresponding authors.
- 2School of Pharmaceutical Science, Liaoning University, Shenyang 110036, China
Abstract
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 Fe 2+ /Fe 3+ 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.
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BibTeX
@article{li2026spatiotemporally,
title = {{Spatiotemporally stratified nanoassemblies for precisely halting the immunothrombotic vicious cycle in acute lung inflammation}},
author = {Cong Li and Yuqing Ni and Jianqiang Huang and Jing Li and Yuqing Zheng and Yifan Zhang and Lianrui Cao and Zeyu Wang and Lijiang Chen},
journal = {Asian Journal of Pharmaceutical Sciences},
year = {2026},
month = sep,
doi = {10.1016/j.ajps.2026.101203},
url = {https://doi.org/10.1016/j.ajps.2026.101203},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Spatiotemporally stratified nanoassemblies for precisely halting the immunothrombotic vicious cycle in acute lung inflammation
AU - Cong Li
AU - Yuqing Ni
AU - Jianqiang Huang
AU - Jing Li
AU - Yuqing Zheng
AU - Yifan Zhang
AU - Lianrui Cao
AU - Zeyu Wang
AU - Lijiang Chen
PY - 2026
DA - 2026/09/23
JO - Asian Journal of Pharmaceutical Sciences
DO - 10.1016/j.ajps.2026.101203
UR - https://doi.org/10.1016/j.ajps.2026.101203
AB - 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 Fe 2+ /Fe 3+ 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.
SN - 1818-0876
SN - 2221-285X
ER -