Inhalable Food-Grade MOFs Loaded Gas Messenger for Acute Lung Injury Treatment by Pulmonary Delivery

Acute lung injury (ALI) is a serious clinical disease the severe stage of which develops into acute respiratory distress syndrome (ARDS), with a high mortality rate of 35 to 40%. Despite decades of research and development of drugs such as corticosteroids and β-2 adrenergic agonists, treatment efficacy has been limited due to an insufficient drug concentration reaching the lungs. Here, a food-grade γ-cyclodextrin-based metal-organic framework (γCD-MOF) modified with cholesterol (CHS) is developed to load sulfur dioxide (SO₂) as a dry powder inhaler (DPI) platform (CHS-CD-MOF@SO₂) for ALI treatment. CHS-CD-MOF@SO₂ has suitable storage stability and excellent aerodynamic characteristics, with a fine particle fraction (FPF) of 40%, a geometric standard deviation (GSD) value of 1.61, and a mass median aerodynamic diameter (MMAD) of 4.8 μm, which can effectively target the lungs. By employing rhodamine B (RhB) as a fluorescence indicator, in vivo fluorescence imaging confirms the superior lung-targeting capability of CHS-CD-MOFs. CHS-CD-MOF@SO₂ can release 92.3 ± 4.4% of SO₂ in PBS solution within 5 min. What's more, the permeability of simulated lung fluid within 30 min is as high as 85%, which has the potential for rapid treatment of ALI. In an ALI mouse model, CHS-CD-MOF@SO₂ reduces the expression of pro-inflammatory factors tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 by regulating the P38 and nuclear factor kappa B (NF-κB) pathways. It also significantly improves the lung tissue dry/wet ratio and reduces neutrophil infiltration. Importantly, this treatment achieves therapeutic outcomes in key efficacy parameters that was comparable to or better than those of dexamethasone (DXMS), a frontline drug for ALI, underscoring its significant therapeutic potential. This study presents a novel strategy for treating ALI using a DPI-based gas messenger platform. This study provides a novel therapeutic strategy to treat ALI using DPI-loaded gas messengers.