Engineering Lipid Nanoparticles to Enhance Intracellular Delivery of Transforming Growth Factor-Beta siRNA (siTGF-β1) via Inhalation for Improving Pulmonary Fibrosis Post-Bleomycin Challenge
<b>Background/Objectives:</b> Transforming Growth Factor-beta (<i>TGFβ1</i>) plays a core role in the process of pulmonary fibrosis (PF). The progression of pulmonary fibrosis can be alleviated by siRNA-based inhibiting <i>TGF-β1</i>. However, the limitations of n...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
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| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/17/2/157 |
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| Summary: | <b>Background/Objectives:</b> Transforming Growth Factor-beta (<i>TGFβ1</i>) plays a core role in the process of pulmonary fibrosis (PF). The progression of pulmonary fibrosis can be alleviated by siRNA-based inhibiting <i>TGF-β1</i>. However, the limitations of naked siRNA lead to the failure of achieving therapeutic effect. This study aimed to design lipid nanoparticles (LNPs) that can deliver si<i>TGF-β1</i> to the lungs for therapeutic purposes. <b>Methods:</b> The cytotoxicity and transfection assay in vitro were used to screen ionizable lipids (ILs). Design of Experiments (DOE) was used to obtain novel LNPs that can enhance resistance to atomization shear forces. Meanwhile, the impact of LNPs encapsulating si<i>TGF-β1</i> (si<i>TGFβ1</i>-LNPs) on PF was investigated. <b>Results:</b> When DLin-DMA-MC3 (MC3) was used as the ILs, the lipid phase ratio was MC3:DSPC:DMG-PEG2000:cholesterol = 50:10:3:37, and N/P = 3.25; the <i>siTGFβ1</i>-LNPs could be stably delivered to the lungs via converting the <i>siTGFβ1</i>-LNPs solution into an aerosol (atomization). In vitro experiments have confirmed that si<i>TGFβ1</i>-LNPs have high safety, high encapsulation, and can promote cellular uptake and endosomal escape. In addition, si<i>TGFβ1</i>-LNPs significantly reduced inflammatory infiltration and attenuated deposition of extracellular matrix (ECM) and protected the lung tissue from the toxicity of bleomycin (BLM) without causing systemic toxicity. <b>Conclusions:</b> The si<i>TGFβ1</i>-LNPs can be effectively delivered to the lungs, resulting in the silencing of <i>TGF-β1</i> mRNA and the inhibition of the epithelial–mesenchymal transition pathway, thereby delaying the process of PF, which provides a new method for the treatment and intervention of PF. |
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| ISSN: | 1999-4923 |