Inhaled Administration of Therapeutic siRNA for Pulmonary Fibrosis: CD105 as a Novel Molecular Target

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TGFβ1 and CD105, a component of its receptor complex, are key drivers of fibrosis. In this study, we investigated the role of TGFβ1/CD105 signaling and the efficacy of silencing CD105 to counteract the fibrotic process. We evaluated the safety and efficacy of inhalable nanoparticle (hNP) designed to deliver siCD105 in vitro and in vivo models of lung fibrosis. TGFβ1 and CD105 expression increased in A549 cells stimulated with LPS (10 μg/mL, 24h), suggesting their involvement in the fibrotic process. The safety of a new hNP formulation, DODMA, specifically designed to deliver siCD105, was evaluated in A549 cells. No cytotoxicity was observed at 24, 48, and 72h. Cellular uptake of unloaded-DODMA (0.5–1 mg/mL) in A549 cells after 24h of exposure confirmed its ability to cross lung barriers. Gene silencing activity of siCD105-loaded DODMA (10nM) was assessed by transfecting A549 cells for 48h, followed by LPS challenge (24h). LPS increased CD105 and TGFβ1 expression, while siCD105-loaded DODMA restored their expressions to basal levels. As proof of concept, we characterized CD105 in an in vivo pulmonary fibrosis model induced by intratracheal administration of bleomycin (4U/Kg) in mice. After 7 days bleomycin increased TGFβ1 and CD105 expression along with pro-fibrotic markers in lung homogenates. Intratracheal co-administration of siCD105-loaded DODMA (0.05nmol/mouse) restored normal levels of TGF-β1, CD105 and pro-fibrotic markers. Collectively, these findings identify CD105 as a potential therapeutic target in pulmonary fibrosis and demonstrate the efficacy of inhaled siCD105-loaded hNP in targeting CD105, offering a new pharmacological strategy.

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