Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea.
Nanoscale. 2020 Mar 21;12(11):6385-6393. doi: 10.1039/c9nr10305h. Epub 2020 Mar 5.
Skin fibrosis occurs in a variety of human diseases but the current anti-fibrosis treatments are not sufficient. One major cause of fibrotic diseases shared across diverse organ fibrosis is uncontrolled overexpression of the connective tissue growth factor (CTGF, also known as CCN2). Here, we examine the anti-fibrotic activity of RNAi therapy utilizing siRNA against CTGF with a new drug delivery system (DDS), 'DegradaBALL', which is based on porous nanoparticles, for durable CTGF gene silencing. DegradaBALL is a modular DDS having many favorable properties for RNA delivery such as effective intracellular uptake, convenient drug loading, biocompatibility, sustained release profile and biodegradability. DegradaBALL loaded with siCTGF, named 'LEM-S401', showed highly durable and effective CTGF gene-silencing in TGF-β induced lung fibrosis and skin fibrosis model cells, A549 and HaCaT, respectively. In addition, LEM-S401 induced knockdown of collagen types I and III, which are excess extracellular matrix components in fibrotic skin in addition to CTGF in the mouse wound healing model. Most importantly, we showed that LEM-S401 effectively inhibited the formation of hypertrophic scars in wound-associated dermal fibrosis mouse models, during both the epidermis recovery and tissue remodeling process. Our findings suggest that LEM-S401 could be a highly potent therapeutic option for skin fibrotic diseases.
皮肤纤维化发生在多种人类疾病中，但目前的抗纤维化治疗方法并不充分。多种器官纤维化中纤维性疾病的一个主要共同原因是结缔组织生长因子（CTGF，也称为 CCN2）的不受控制的过度表达。在这里，我们利用针对 CTGF 的 siRNA 检查了利用新的药物输送系统（DDS）“DegradaBALL”的 RNAi 治疗的抗纤维化活性，该 DDS 基于多孔纳米颗粒，可实现持久的 CTGF 基因沉默。DegradaBALL 是一种模块化 DDS，具有许多有利于 RNA 递送的特性，例如有效的细胞内摄取、方便的药物加载、生物相容性、持续释放曲线和生物降解性。用 siCTGF 装载的 DegradaBALL，命名为“LEM-S401”，在 TGF-β诱导的肺纤维化和皮肤纤维化模型细胞 A549 和 HaCaT 中分别表现出高度持久和有效的 CTGF 基因沉默。此外，LEM-S401 诱导了 I 型和 III 型胶原的下调，这些胶原是纤维化皮肤中除 CTGF 之外的过量细胞外基质成分。最重要的是，我们表明 LEM-S401 有效抑制了与伤口相关的真皮纤维化小鼠模型中肥厚性瘢痕的形成，在表皮恢复和组织重塑过程中均如此。我们的研究结果表明，LEM-S401 可能是治疗皮肤纤维化疾病的一种非常有效的治疗选择。
