Gene Regulation Using Spherical Nucleic Acids to Treat Skin Disorders

Abstract

Spherical nucleic acids (SNAs) are nanostructures consisting of nucleic acids in a spherical configuration, often around a nanoparticle core. SNAs are advantageous as gene-regulating agents compared to conventional gene therapy owing to their low toxicity, enhanced stability, uptake by virtually any cell, and ability to penetrate the epidermal barrier. In this review we: (i) describe the production, structure and properties of SNAs; (ii) detail the mechanism of SNA uptake in keratinocytes, regulated by scavenger receptors; and (iii) report how SNAs have been topically applied and intralesionally injected for skin disorders. Specialized SNAs called nanoflares can be topically applied for gene-based diagnosis (scar vs. normal tissue). Topical SNAs directed against TNFα and interleukin-17A receptor reversed psoriasis-like disease in mouse models and have been tested in Phase 1 human trials. Furthermore, SNAs targeting ganglioside GM3 synthase accelerate wound healing in diabetic mouse models. Most recently, SNAs targeting toll-like receptor 9 are being used in Phase 2 human trials via intratumoral injection to induce immune responses in Merkel cell and cutaneous squamous cell carcinoma. Overall, SNAs are a valuable tool in bench-top and clinical research, and their advantageous properties, including penetration into the epidermis after topical delivery, provide new opportunities for targeted therapies.

Spherical nucleic acids: Organized nucleotide aggregates as versatile nanomedicine

“…Completed trials have shown no serious adverse events, mild injection site reactions and flu‐like symptoms, dose‐related systemic immune activation, and more diverse tumor cell infiltration with AST‐008 injection compared to noninjected tumors. [ 95 ] As such, additional immunostimulatory SNAs consisting of RNAs selective for TLR‐7/8 were synthesized and characterized. [ 50 ]…”

“…Rosi et al first demonstrated that SNAs could enter cells and regulate gene expression using single-stranded DNA. [ 94 , 95 ] Since then, double-stranded DNA, siRNA, or miRNA conjugates have been applied to SNAs. [ 92 , 96 – 98 ] The aggregation of surface oligonucleotides will determine SNA’s biological behaviors from the moment they interact with cells in vitro or organs in vivo.…”

“…[ 188 ] SNAs have been shown to be efficacious in penetrating uniformly thickened skin, knocking down gene targets, and reversing skin disease in mouse and human three-dimensional culture models of psoriasis. [ 13 , 95 ] Phase I clinical trials have shown the safety and promise of SNAs as topical agents against TNF- α and interleukin 17 receptor A (IL17RA), the inhibitory targets against moderate to severe psoriasis. [ 11 ] The two drugs involved are named AST-005 and XCUR17, respectively.…”

“…AST-005 resulted in a significant reduction in TNF- α , while XCUR17 had no IL17RA knockdown but reduced gene expression of K16 and inflammation. [ 95 ] This suggests a very promising clinical pathway for SNA-based local treatments.…”

Cellular Export Fate of Liposomal Spherical Nucleic Acids

“…For example, LSNAs prepared from oligonucleotide-phospholipid conjugates have been shown to possess high serum stability and display higher cell uptake as compared to LSNAs synthesized using cholesterol terminated (anchoring) oligonucleotides . Moreover, these structures are medically relevant and thus far have been the basis for 6 clinical trials. − …”