An Inhalable Hybrid Biomimetic Nanoplatform for Sequential Drug Release and Remodeling Lung Immune Homeostasis in Acute Lung Injury Treatment.
Chang LiuLong XiYihan LiuJudith Choi Wo MakShirui MaoZhenping WangYing ZhengPublished in: ACS nano (2023)
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 dual-stage drug release behavior facilitated down-regulation of pro-inflammatory cytokines in the lung but anti-inflammatory cytokine production through remodeling lung immune homeostasis, ultimately promoting lung tissue repair. This work presents a versatile hybrid biomimetic nanoplatform for the local pulmonary delivery of dual-drug therapeutics and displays potential in the treatment of acute inflammation.
Keyphrases
- drug release
- acute respiratory distress syndrome
- lps induced
- drug delivery
- stem cells
- anti inflammatory
- inflammatory response
- cancer therapy
- signaling pathway
- photodynamic therapy
- extracorporeal membrane oxygenation
- cystic fibrosis
- oxidative stress
- mechanical ventilation
- combination therapy
- toll like receptor
- lipopolysaccharide induced
- metabolic syndrome
- pulmonary hypertension
- adipose tissue
- high dose
- small molecule
- drug induced
- type diabetes
- low dose
- climate change
- immune response
- insulin resistance
- fluorescent probe
- skeletal muscle
- sensitive detection
- adverse drug