Randeria Pratik S, Seeger Mark A, Wang Xiao-Qi, Wilson Heather, Shipp Desmond, Mirkin Chad A, Paller Amy S
Departments of Biomedical Engineering and International Institute for Nanotechnology, Northwestern University, Evanston, IL 60208; and.
Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Proc Natl Acad Sci U S A. 2015 May 5;112(18):5573-8. doi: 10.1073/pnas.1505951112. Epub 2015 Apr 20.
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.
分散在凡士林（Aquaphor）中的球形核酸（SNA）金纳米颗粒偶联物（直径13纳米的金核，表面密集排列且高度定向地功能化有核酸）已被证明能穿透完整小鼠和人类皮肤的表皮屏障，进入角质形成细胞，并有效下调基因靶点。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在正常血糖和高血糖条件下均能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。在饮食诱导的肥胖糖尿病小鼠中，将GM3S SNA（50 nM）局部应用于直径6毫米的全层夹板伤口，通过小干扰RNA（siRNA）途径使伤口边缘的局部GM3S表达降低>80%，并在12天内实现临床和组织学上的伤口完全愈合，而对照处理的伤口仅愈合50%。GM3S SNA处理的伤口中肉芽组织面积、血管生成以及IGF1和表皮生长因子（EGF）受体磷酸化均增加。这些数据利用了SNA独特的天然穿透皮肤并进入角质形成细胞的能力，而无需转染试剂。此外，这些数据进一步验证了GM3作为2型糖尿病伤口愈合延迟的介质，并支持局部GM3消耗作为一个有前景的治疗方向。
