siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown
siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown
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DOI：
10.1073/pnas.1505951112
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发表时间：
2015-05-05
影响因子：
11.1
通讯作者：
Paller, Amy S.
中科院分区：
文献类型：
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作者：
Randeria, Pratik S.;Seeger, Mark A.;Paller, Amy S.
分散在 Aquaphor 中的球形核酸 (SNA) 金纳米颗粒缀合物（直径为 13 纳米的金核，由密集且高度定向的核酸功能化）已被证明可以穿透完整小鼠和人类皮肤的表皮屏障，进入角质形成细胞，并有效下调目标基因。神经节苷脂单唾液酸 3 合酶 (GM3S) 是一个已知靶点，在糖尿病小鼠中过度表达，导致胰岛素抵抗并阻碍伤口愈合。 GM3S SNA 在正常和高血糖条件下均可增加角质形成细胞的迁移和增殖以及胰岛素和胰岛素样生长因子 1 (IGF1) 受体的激活。将 GM3S SNA (50 nM) 局部应用到饮食诱导的肥胖糖尿病小鼠的夹板直径 6 毫米的全层伤口上，通过 siRNA 途径将伤口边缘的局部 GM3S 表达降低了 80% 以上，并在 12 天内临床和组织学上完全治愈伤口，而对照治疗的伤口仅闭合 50%。 GM3S SNA 处理的伤口中，肉芽组织面积、血管分布以及 IGF1 和 EGF 受体磷酸化均增加。这些数据利用了 SNA 无需转染剂即可自然穿透皮肤并进入角质形成细胞的独特能力。此外，数据进一步验证了 GM3 作为 2 型糖尿病伤口愈合延迟的介质，并支持区域 GM3 耗竭作为一个有前途的治疗方向。
Spherical nucleic acid (SNA) gold nanoparticle conjugates (13-nm-diameter gold cores functionalized with densely packed and highly oriented nucleic acids) dispersed in Aquaphor have been shown to penetrate the epidermal barrier of both intact mouse and human skin, enter keratinocytes, and efficiently down-regulate gene targets. ganglioside-monosialic acid 3 synthase (GM3S) is a known target that is overexpressed in diabetic mice and responsible for causing insulin resistance and impeding wound healing. GM3S SNAs increase keratinocyte migration and proliferation as well as insulin and insulin-like growth factor-1 (IGF1) receptor activation under both normo-and hyperglycemic conditions. The topical application of GM3S SNAs (50 nM) to splinted 6-mm-diameter full-thickness wounds in diet-induced obese diabetic mice decreases local GM3S expression by > 80% at the wound edge through an siRNA pathway and fully heals wounds clinically and histologically within 12 d, whereas control-treated wounds are only 50% closed. Granulation tissue area, vascularity, and IGF1 and EGF receptor phosphorylation are increased in GM3S SNA-treated wounds. These data capitalize on the unique ability of SNAs to naturally penetrate the skin and enter keratinocytes without the need for transfection agents. Moreover, the data further validate GM3 as a mediator of the delayed wound healing in type 2 diabetes and support regional GM3 depletion as a promising therapeutic direction.