Immuno-modulatory spherical nucleic acids (SNAs) have shown great promise in activating and suppressing toll-like receptor (TLR) 9 for applications in anti-tumor immunity and autoimmune diseases. In addition to TLR 9, there are three other endosomal TLRs (3, 7, and 8), which are responsible for recognizing double and single stranded RNA. Since various antigen-presenting cells (APCs) have differential TLR expression levels, targeting multiple TLRs can activate more types of immune cells, and also synergistically improve tumor eradication in vivo. Currently, potent small molecule TLR 7/8 agonists (i.e. resiquimod) are limited to topical applications due to significant toxicity caused by off-targeting effects and systemic immune activation. On the other hand, RNA-based TLR 7/8 agonists, while specific, can be easily degraded by nucleases and lack an efficient means of cellular uptake. This project focuses on using liposomal SNAs to activate TLR 3, 7 and 8 via RNA immuno-stimulatory oligonucleotides. Due to their dense oligonucleotide shell, SNAs exhibit increased interactions with cell surface proteins resulting in high cellular uptake in virtually all cell lines while localizing mainly in endosomal compartments, decreased activity of endonucleases on the nanoparticle surface due to a high local salt concentration, and also no cytotoxicity. As a result, SNAs are perfectly suited to act as single-entity RNA agonists for activating APCs. We show that these RNA based immuno-stimulatory SNAs (IS-SNAs) exhibit over 30-fold increase of secreted NF-kB in murine macrophages compared to the free strand delivered using a cationic transfection agent (no activation was seen with just the free stand). In addition, treatment of mouse dendritic cells with RNA-based IS-SNAs in the presence of model tumor antigen improves the rate of antigen presentation, which is an important step in immunizing against cancer. This observation sets the foundation for the development of novel RNA-SNA based antitumor vaccines.

RNA-based immuno-stimulatory liposomal spherical nucleic acids for antigen presenting cell activation

250th National Meeting (2015)

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