siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown
Authors
Pratik S. Randeria, Mark A. Seeger, Xiao-Qi Wang, Heather Wilson, Desmond Shipp, Chad A. Mirkin and Amy S. Paller
Institution
Northwestern University
Country
United States
Year
2015
Journal
PNAS
Abstract
Spherical nucleic acid (SNA) gold nanoparticle conjugates (13-nmdiameter
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 thewound 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.