Mucopenetrative Lipid–Polymer nanoparticles show Potent Anti-Inflammatory activity in a human Lung-on-Chip model
Year: 2026
Type: article
Abstract: Airway mucus presents a significant barrier to inhaled drug delivery, particularly for nanoparticle-based interventions, with this barrier exacerbated in chronic respiratory diseases (CRDs) due to hyperviscous secretions and persistent inflammation. In this study, a dual-functional lipid-polymer hybrid nanoparticle was developed to combine rapid mucolysis with sustained anti-inflammatory activity, and its performance was evaluated using both conventional in vitro assays and a physiologically relevant lung-on-a-chip model. Dipalmitoylphosphatidylcholine (DPPC)-coated PLGA nanoparticles (hydrodynamic diameter 378.1 ± 23.0 nm; 58-61 wt% lipid; ζ ≈ +3 mV) encapsulated N-acetylcysteine (NAC) within the lipid shell for rapid release and all-trans retinoic acid (ATRA) within the core for sustained delivery. NAC exhibited a burst release of 44.2-52.5% within 6 h and significantly reduced the viscosity of cystic fibrosis-mimetic mucus, enabling a 26.5-fold higher penetration across a ∼ 0.6 mm mucus plug compared to NAC-free controls. The formulation was well tolerated by pulmonary epithelial and fibroblast cells and demonstrated high cellular uptake driven by the DPPC coating. To assess efficacy under physiologically relevant airway conditions, a human lung-on-a-chip model incorporating air-liquid interface, flow, and cyclic stretch was employed. In this model, repeated dosing of NAC + ATRA nanoparticles resulted in a 2.6-fold reduction in IL-6 and a 2.3-fold reduction in IL-8 levels compared to diseased controls at 72 h, outperforming NAC-free nanoparticles at early timepoints and maintaining suppression over 9 days. These findings demonstrate the therapeutic promise of dual-functional mucopenetrative nanoparticles and establish the utility of lung disease-on-chip platforms for evaluating inhaled nanotherapeutics under physiologically relevant conditions.
Institutions: University of Rhode Island, Texas A&M University
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,650
Funders: Warwick City Hall, National Science Foundation, University of Rhode Island, United States Atomic Energy Commission, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, National Cancer Institute, National Institute of General Medical Sciences, Office of Experimental Program to Stimulate Competitive Research
Awards: RII Track-1: Rhode Island Consortium for Coastal Ecology Assessment, Innovation, and Modeling, G239728837, G3987022041, G473475532, RI Network for Excellence in Biomedical and Behavioral Research, MRI: Acquisition of a Scanning/Transmission Electron Microscope for Materials Research and Education, G8042061648, G8225992533, G8700853992, G9000051754, G9000111253, Multifunctional Nanoparticle Platform to Prevent Alcohol-Associated HCC Development
OpenAlex ID: W7130503578