title: siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown.
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.
authors.affiliation: Departments of Biomedical Engineering and International Institute for Nanotechnology, Northwestern University, Evanston, IL 60208; and.
authors.forename: Pratik S
authors.initials: PS
authors.lastname: Randeria
authors.affiliation: Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Seeger
authors.affiliation: Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Xiao-Qi
authors.initials: XQ
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Heather
authors.initials: H
authors.lastname: Wilson
authors.affiliation: Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Desmond
authors.initials: D
authors.lastname: Shipp
authors.affiliation: Departments of Biomedical Engineering and International Institute for Nanotechnology, Northwestern University, Evanston, IL 60208; and Chemistry and chadnano@northwestern.edu apaller@northwestern.edu.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Mirkin
authors.affiliation: Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 chadnano@northwestern.edu apaller@northwestern.edu.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Paller
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism; D005679:G(M3) Ganglioside / Q000737:chemistry*; D006046:Gold / Q000737:chemistry; D006801:Humans; D008297:Male; D053768:Metal Nanoparticles / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009696:Nucleic Acids / Q000737:chemistry*; D015202:Protein Engineering; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D012799:Sialyltransferases / Q000235:genetics* / Q000378:metabolism; D014945:Wound Healing
chemical_list: D005679:G(M3) Ganglioside; D009696:Nucleic Acids; D034741:RNA, Small Interfering; D006046:Gold; D012799:Sialyltransferases; C021343:haematoside synthetase; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1
keywords: GM3 synthase; SNA; diabetic wound healing; nanoparticle; siRNA