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Contributed by Chad A. Mirkin, March 25, 2015 (sent for review February 13, 2015; reviewed by Dean Ho and Wei Li)
Significance
Diabetic patients often suffer from impaired wound healing, which can develop into nonhealing diabetic ulcers, facilitate bacterial infections, and necessitate amputation. Current strategies for treatment have failed to achieve the anticipated efficacy and do not address the fundamental molecular abnormalities that prevent efficient wound closure. In this work, we introduce a previously unidentified approach to treating diabetic wound healing by using topically delivered spherical nucleic acids to effect the knockdown of ganglioside-monosialic acid 3 (GM3) synthase, a mediator of impaired wound healing, in type 2 diabetic mice. In addition to laying the groundwork for developing a therapy for a debilitating condition, this work also validates the critical role of GM3 in diabetic wound healing.
Abstract
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.
Footnotes
- ↵1To whom correspondence may be addressed. Email: chadnano{at}northwestern.edu or apaller{at}northwestern.edu.
Author contributions: P.S.R., M.A.S., C.A.M., and A.S.P. designed research; P.S.R., M.A.S., X.-Q.W., H.W., and D.S. performed research; P.S.R., M.A.S., X.-Q.W., C.A.M., and A.S.P. analyzed data; and P.S.R., M.A.S., X.-Q.W., C.A.M., and A.S.P. wrote the paper.
Reviewers: D.H., University of California, Los Angeles; and W.L., University of Southern California.
Conflict of interest statement: C.A.M. is a cofounder of Aurasense Therapeutics, LLC, and A.S.P. is on the advisory board of Aurasense Therapeutics, LLC.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1505951112/-/DCSupplemental.
GM3S SNAs reverse diabetic wound healing
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