Pulmonary Delivery of Specialized Pro-Resolving Mediators-Based Nanotherapeutics Attenuates Pulmonary Fibrosis in Preclinical Animal Models.
Jiulong LiYu XiaoYumo ZhangSilu LiMinzhi ZhaoTian XiaHuan MengPublished in: ACS nano (2023)
Pulmonary fibrosis (PF) is a chronic lung disease characterized by excess extracellular matrix deposition and prolonged inflammation that fails to resolve and is druggable. Using resolvins and their precursors for inflammation resolution, we demonstrate a nano-enabled approach for accomplishing robust antifibrotic effects in bleomycin- or engineered nanomaterial-induced mouse and rat PF models. Targeting the lipid peroxidation-triggered NLRP3 inflammasome and NF-κB pathway in macrophages and the ROS-mediated TGF-β/Smad and S1P signaling in epithelial cells results in these potent protective effects at the ng/mL dosimetry. We further develop an inhalable biocompatible nanoparticle that encapsulates fish oil, a chosen resolvin precursor, with phosphatidylcholine and polyethylene glycol to enhance drug permeability and facilitate crossing the mucosal barrier, forming " fish -oilsome" (FOS). Oropharyngeal aspiration and inhalation of FOS improved the anti-inflammatory status, histological characteristics, and pulmonary function in fibrotic lungs, which was mechanistically supported by transcriptomic and proteomic analyses. Further, scale-up engineered FOS samples with the desired physicochemical properties, anti-PF efficacy, and in vivo biocompatibility were validated in different batch sizes (up to 0.2 L/batch). This study provides a practical and translatable approach to promoting inflammation resolution and PF treatment.
Keyphrases
- pulmonary fibrosis
- oxidative stress
- anti inflammatory
- extracellular matrix
- nlrp inflammasome
- diabetic rats
- transforming growth factor
- dna damage
- single molecule
- signaling pathway
- drug induced
- pulmonary hypertension
- palliative care
- systemic sclerosis
- epithelial mesenchymal transition
- fatty acid
- single cell
- idiopathic pulmonary fibrosis
- pi k akt
- stem cells
- anaerobic digestion
- immune response
- inflammatory response
- reactive oxygen species
- lps induced
- adverse drug
- toll like receptor