Development of a Lipid-encapsulated TGFβRI-siRNA Drug for Liver Fibrosis Induced by Schistosoma mansoni

• Published in: PLoS neglected tropical diseases 2024-09, Vol.18 (9), p.e0012502
• Main Authors: Chen, Ying-Chou, Lee, Yueh-Lun, Lee, Ching-An, Lin, Tzu-Yuan, Hwu, Edwin En-Te, Cheng, Po-Ching
• Format: Article
• Language: English
• Subjects: Biology and life sciences; Medicine and Health Sciences; Research and Analysis Methods
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0012502

Schistosoma mansoni infection leads to chronic schistosomiasis and severe hepatic fibrosis. We designed a liver-targeted lipid nanoparticle (LNP) carrying siRNA against type I TGF-β receptor (TGFβRI) mRNA to treat schistosomiasis-induced liver fibrosis in BALB/c mice. Knockdown of TGFβRI by LNP-siTGFβRI reduced LX-2 cell activation in vitro and alleviated liver fibrosis in S. mansoni-infected mice. αSMA and Col1a1 fibrotic markers in the liver tissues of infected mice were significantly suppressed in the treatment groups. In the serum of the LNP-siTGFβRI-treated groups, cytokines IFNγ, IL-1α, IL-6, IL-12, RANTES (CCL5), and TNFα increased, while GM-CSF, IL-2, IL-4, IL-10, IL-13, and KC (CXCL1) decreased compared to the control. Cell proportions were significantly altered in S. mansoni-infected mice, with increased CD56d NK cells and decreased CD19+ B cells and CD4+ T cells compared to naïve mice. Following LNP-siTGFβRI treatment, CD56d NK cells were downregulated, while B and memory Th cell populations were upregulated. The density of fibrotic regions significantly decreased with LNP-siTGFβRI treatment in a dose-dependent manner, and no systemic toxicity was observed in the major organs. This targeted siRNA delivery strategy effectively reduced granulomatous lesions in schistosomiasis-induced liver fibrosis without detectable side effects.