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

IF 3.8 2区医学 Q1 Medicine

PLoS Neglected Tropical Diseases Pub Date : 2024-09-12 DOI:10.1371/journal.pntd.0012502

Ying-Chou Chen, Yueh-Lun Lee, Ching-An Lee, Tzu-Yuan Lin, Edwin En-Te Hwu, Po-Ching Cheng

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引用次数: 0

Abstract

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.

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开发治疗曼氏血吸虫诱发的肝纤维化的脂质包裹 TGFβRI-siRNA 药物

曼氏血吸虫感染会导致慢性血吸虫病和严重的肝纤维化。我们设计了一种携带针对 I 型 TGF-β 受体（TGFβRI）mRNA siRNA 的肝脏靶向脂质纳米粒子（LNP），用于治疗血吸虫诱导的 BALB/c 小鼠肝纤维化。LNP-siTGFβRI敲除TGFβRI可减少体外LX-2细胞活化，缓解曼氏血吸虫感染小鼠的肝纤维化。与对照组相比，LNP-siTGFβRI处理组血清中细胞因子IFNγ、IL-1α、IL-6、IL-12、RANTES（CCL5）和TNFα增加，而GM-CSF、IL-2、IL-4、IL-10、IL-13和KC（CXCL1）减少。与天真小鼠相比，曼氏沙门氏菌感染小鼠的细胞比例明显改变，CD56d NK 细胞增加，CD19+ B 细胞和 CD4+ T 细胞减少。经 LNP-siTGFβRI 处理后，CD56d NK 细胞下调，而 B 细胞和记忆 Th 细胞群上调。LNP-siTGFβRI治疗后，纤维化区域的密度明显降低，且呈剂量依赖性，在主要器官中未观察到全身毒性。这种靶向 siRNA 递送策略可有效减少血吸虫诱导的肝纤维化中的肉芽肿病变，且无明显副作用。

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来源期刊

PLoS Neglected Tropical Diseases Medicine-Infectious Diseases

CiteScore

7.40

自引率

10.50%

发文量

723

审稿时长

2-3 weeks

期刊介绍： PLOS Neglected Tropical Diseases publishes research devoted to the pathology, epidemiology, prevention, treatment and control of the neglected tropical diseases (NTDs), as well as relevant public policy. The NTDs are defined as a group of poverty-promoting chronic infectious diseases, which primarily occur in rural areas and poor urban areas of low-income and middle-income countries. Their impact on child health and development, pregnancy, and worker productivity, as well as their stigmatizing features limit economic stability. All aspects of these diseases are considered, including: Pathogenesis Clinical features Pharmacology and treatment Diagnosis Epidemiology Vector biology Vaccinology and prevention Demographic, ecological and social determinants Public health and policy aspects (including cost-effectiveness analyses).