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Development of a Lipid-encapsulated TGFβRI-siRNA Drug for Liver Fibrosis Induced by Schistosoma mansoni
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Development of a Lipid-encapsulated TGFβRI-siRNA Drug for Liver Fibrosis Induced by Schistosoma mansoni
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Journal Article
Development of a Lipid-encapsulated TGFβRI-siRNA Drug for Liver Fibrosis Induced by Schistosoma mansoni
2024
Overview
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.
Publisher
Public Library of Science
