An Inhalable Hybrid Biomimetic Nanoplatform for Sequential Drug Release and Remodeling Lung Immune Homeostasis in Acute Lung Injury Treatment

作者：Chang Liu, Long Fu Xi, Yihan Liu, Jcw Mak, Shirui Mao, Zhenping Wang, Ying Zheng · 发表于：ACS Nano · 年份：2023 · DOI：10.1021/acsnano.3c02075 · 被引用次数：107 · 研究领域：Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Neonatal Respiratory Health Research、Immune cells in cancer

Interactions of lung macrophages and recruited neutrophils with the lung microenvironment continuously aggravate the dysregulation of lung inflammation in the pathogenesis of acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Either modulating macrophages or destroying neutrophil counts cannot guarantee a satisfactory outcome in ARDS treatment. Aimed at inhibiting the coordinated action of neutrophils and macrophages and modulating the hyper-inflammatory condition, an inhalable biomimetic sequential drug-releasing nanoplatform was developed for the combinatorial treatment of ALI. The nanoplatform (termed D-SEL) was made by conjugating DNase I, as outer cleavable arms, to a serum exosomal and liposomal hybrid nanocarrier (termed SEL) via a matrix metalloproteinase 9 (MMP-9)-cleavable peptide and then encapsulating methylprednisolone sodium succinate (MPS). In lipopolysaccharide (LPS) induced ALI in mice, the MPS/D-SEL moved through muco-obstructive airways and was retained in the alveoli for over 24 h postinhalation. DNase I was then released from the nanocarrier first after responding to MMP-9, resulting in inner SEL core exposure, which precisely delivered MPS into macrophages for promoting M2 macrophage polarization. Local and sustained DNase I release degraded dysregulated neutrophil extracellular traps (NETs) and suppressed neutrophil activation and the mucus plugging microenvironment, which in turn amplified M2 macrophage polarization efficiency. Such...