Dual knockdown of Alox15 and TGF-β1 by lipid nanoparticle-delivered siRNA in bleomycin-induced pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is associated with high morbidity and mortality, highlighting the urgent need for more effective treatments with fewer adverse effects. Small interfering RNA (siRNA) delivered via lipid nanoparticles (LNP) has shown both safety and therapeutic potential as a novel treatment strategy. Alox15 and TGF-β1 were both upregulated in the lung tissues of IPF patients and bleomycin-induced mice. LNP-delivered siRNAs demonstrated superior tissue distribution and efficacy in targeting molecules upregulated in IPF compared to naked siRNAs, and were used to treat bleomycin-induced pulmonary fibrosis in mice. Dual knockdown of Alox15 and TGF-β1 was achieved using LNP-delivered dual siRNAs, leading to significant improvements in lung function, reduced fibrosis severity, and decreased hydroxyproline content. Knockdown of either Alox15 or TGF-β1 alone also ameliorated pulmonary fibrosis, but the combined knockdown produced a more pronounced therapeutic effect. These results demonstrate that dual knockdown of Alox15 and TGF-β1 via LNP-delivered siRNAs effectively targets bleomycin-induced IPF, representing a promising therapeutic strategy for this disease. • LNP-delivered siRNA enables efficient lung targeting in pulmonary fibrosis. • Alox15 and TGF-β1 are co-upregulated in IPF patients and fibrotic mice. • Dual knockdown of Alox15 and TGF-β1 improves lung function and fibrosis. • Combined gene silencing outperforms single-target siRNA therapy.