Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 30, Pages 11975-11980Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1118425109
Keywords
transdermal delivery; nanocluster; antisense; nanotechnology; dermatology
Categories
Funding
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01 AR060810]
- National Center for Research Resources from National Cancer Institute [UL1 RR025741]
- Army Research Office
- Northwestern Skin Disease Research Center [P30AR057216]
- National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases
- Cancer Center Support Grant [NCI CA060553]
- National Center for Research Resources [UL1 RR025741]
- National Science Foundation [CHE-9810378/005]
- National Aernoautics and Space Administration Ames Research Center [NNA04CC36G]
- Center for Cancer Nanotechnology Excellence from National Cancer Institute [U54CA151880]
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Topical application of nucleic acids offers many potential therapeutic advantages for suppressing genes in the skin, and potentially for systemic gene delivery. However, the epidermal barrier typically precludes entry of gene-suppressing therapy unless the barrier is disrupted. We now show that spherical nucleic acid nano-particle conjugates (SNA-NCs), gold cores surrounded by a dense shell of highly oriented, covalently immobilized siRNA, freely penetrate almost 100% of keratinocytes in vitro, mouse skin, and human epidermis within hours after application. Significantly, these structures can be delivered in a commercial moisturizer or phosphate-buffered saline, and do not require barrier disruption or transfection agents, such as liposomes, peptides, or viruses. SNA-NCs targeting epidermal growth factor receptor (EGFR), an important gene for epidermal homeostasis, are >100-fold more potent and suppress longer than siRNA delivered with commercial lipid agents in cultured keratinocytes. Topical delivery of 1.5 uM EGFR siRNA (50 nM SNA-NCs) for 3 wk to hairless mouse skin almost completely abolishes EGFR expression, suppresses downstream ERK phosphorylation, and reduces epidermal thickness by almost 40%. Similarly, EGFR mRNA in human skin equivalents is reduced by 52% after 60 h of treatment with 25 nM EGFR SNA-NCs. Treated skin shows no clinical or histological evidence of toxicity. No cytokine activation in mouse blood or tissue samples is observed, and after 3 wk of topical skin treatment, the SNA structures are virtually undetectable in internal organs. SNA conjugates may be promising agents for personalized, topically delivered gene therapy of cutaneous tumors, skin inflammation, and dominant negative genetic skin disorders.
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