Dermal delivery of HSP47 siRNA with NOX4-modulating mesoporous silica-based nanoparticles for treating fibrosis.
Dermal delivery of HSP47 siRNA with NOX4-modulating mesoporous silica-based nanoparticles for treating fibrosis.
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DOI：
10.1016/j.biomaterials.2015.07.005
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发表时间：
2015-10
期刊：
影响因子：
14
通讯作者：
Yantasee W
中科院分区：
文献类型：
--
作者：
Morry J;Ngamcherdtrakul W;Gu S;Goodyear SM;Castro DJ;Reda MM;Sangvanich T;Yantasee W
硬皮病等纤维化疾病与氧化应激增加和促纤维化基因上调有关。最近的研究表明，NADPH氧化酶4 （NOX4）和热休克蛋白47 （HSP47）在诱导过度胶原合成，导致纤维化疾病中的作用。在此，我们阐明了NOX4和HSP47在纤维化发生中的关系，并提出将它们共同调节作为治疗纤维化的新策略。我们开发了一个由聚乙烯亚胺（PEI）和聚乙二醇（PEG）涂层组成的纳米粒子平台，该平台位于50 nm的介孔二氧化硅纳米粒子（MSNP）核心上。纳米颗粒在TGF-β刺激成纤维细胞的体外纤维化模型中有效递送靶向HSP47 （siHSP47）的小干扰RNA （siRNA）。在体外纤维化模型中，MSNP核心还通过清除活性氧（ROS）并随后降低NOX4水平而赋予抗氧化特性。纳米颗粒在调节促纤维化标志物方面远优于n-乙酰半胱氨酸（NAC）。在博莱霉素诱导的硬皮病小鼠模型中进行了体内评估，该模型与人类硬皮病有许多相似之处。皮内给药sihsp47纳米颗粒有效地将皮肤中的HSP47蛋白表达降低到正常水平。此外，抗氧化MSNP在降低促纤维化标志物NOX4、α-平滑肌肌动蛋白（α-SMA）和I型胶原蛋白（COL I）以及小鼠皮肤厚度方面也发挥了突出作用。
Fibrotic diseases such as scleroderma have been linked to increased oxidative stress and upregulation of pro-fibrotic genes. Recent work suggests a role of NADPH oxidase 4 (NOX4) and heat shock protein 47 (HSP47) in inducing excessive collagen synthesis, leading to fibrotic diseases. Herein, we elucidate the relationship between NOX4 and HSP47 in fibrogenesis and propose to modulate them altogether as a new strategy to treat fibrosis. We developed a nanoparticle platform consisting of polyethylenimine (PEI) and polyethylene glycol (PEG) coating on a 50-nm mesoporous silica nanoparticle (MSNP) core. The nanoparticles effectively delivered small interfering RNA (siRNA) targeting HSP47 (siHSP47) in an in vitro model of fibrosis based on TGF-β stimulated fibroblasts. The MSNP core also imparted an antioxidant property by scavenging reactive oxygen species (ROS) and subsequently reducing NOX4 levels in the in vitro fibrogenesis model. The nanoparticle was far superior to n-acetyl cysteine (NAC) at modulating pro-fibrotic markers. In vivo evaluation was performed in a bleomycin-induced scleroderma mouse model, which shares many similarities to human scleroderma disease. Intradermal administration of siHSP47-nanoparticles effectively reduced HSP47 protein expression in skin to normal level. In addition, the antioxidant MSNP also played a prominent role in reducing the pro-fibrotic markers, NOX4, alpha smooth muscle actin (α-SMA), and collagen type I (COL I), as well as skin thickness of the mice.