Hemoglobin's α-Helix-to-β-Sheet Transition Enables Targeted mRNA Delivery to the Lung

Area of Science:

• Biomaterials Science
• Nanotechnology
• Pulmonary Medicine

Background:

• Effective treatment for pulmonary diseases is limited by the lack of targeted delivery systems.
• Selective tissue targeting is crucial for enhancing therapeutic efficacy and minimizing side effects.

Purpose of the Study:

• To develop a novel lung-targeting platform using repurposed hemoglobin (Hb).
• To evaluate the efficacy of Hb-based nanoparticles (HbFs) for mRNA delivery in a pulmonary fibrosis model.

Main Methods:

• Hemoglobin (Hb) was structurally repurposed via acidic heating to form self-assembled fibrils (HbFs).
• Cryo-electron microscopy (cryo-EM) was used to determine the fibril structure and identify surface properties.
• HbFs were loaded with mRNA encoding IL-11 scFv and administered intravenously in a murine model of bleomycin-induced pulmonary fibrosis.

Main Results:

• Intravenously injected HbFs demonstrated rapid and specific accumulation in the lungs.
• HbFs exhibited a positively charged surface, facilitating platelet binding for lung targeting and mRNA complexation.
• The HbF-mRNA formulation achieved lung-specific delivery, with uptake by pulmonary fibroblasts, leading to sustained IL-11 scFv expression.
• Treatment significantly reduced fibroblast activation, collagen deposition, and improved lung function in the murine model.

Conclusions:

• HbFs represent a novel protein-based vehicle for targeted mRNA delivery to the lungs.
• This platform leverages natural cellular trafficking for localized therapy of lung disorders.
• HbF-based delivery shows promise for treating pulmonary fibrosis and other lung diseases.