Gene Regulation

RNA Interference Antibody-Mediated Signal Cascade Interference

One way that the Day Lab enables high precision therapy is by designing nanoparticles that can suppress the expression of disease-promoting genes through the delivery of antagonistic RNA molecules or antibodies. In RNA interference (depicted above left), nanoparticles are used to deliver RNA molecules into cells. After the nanoparticles escape endosomes and release their RNA cargo into the cytosol (which is not easy to achieve!), the RNA loads into the RNA induced silencing complex (RISC) and guides it to complementary messenger RNA (mRNA) molecules, which are then degraded. We have shown that nanoscale architecture is a critical factor that dictates how cells perceive and respond to RNA nanocarriers, as we demonstrated that the orientation of the molecules in these structures can dramatically influence their efficacy and biocompatibility. In antibody-mediated signal cascade interference (depicted above right), antibodies bind specific receptors on targeted cells to lock them in a ligand unresponsive state, which reduces downstream signaling. We have shown that antibody-nanoparticle conjugates are drastically more effective than freely delivered antibodies, and we attribute this to their ability to engage multiple receptors simultaneously.

To date, we have used antibody and RNA nanocarriers to suppress the developmental Wnt, Notch, and Hedgehog signaling pathways in cancer, with an emphasis on glioblastoma and triple-negative breast cancer. We have also evaluated our nanomaterials as tools for delivery of therapeutic miRNA molecules.

 

Representative Publications

1. Melamed JR, Ioele SA, Hannum AJ, Ullman VM, Day ES. Polyethylenimine-spherical nucleic acid nanoparticles against Gli1 reduce the chemoresistance and stemness of glioblastoma cells. Molecular Pharmaceutics. 2018; 15(11): 5135-5145.

2. Melamed JR, Kreuzberger NL, Goyal R, Day ES. Spherical nucleic acid architecture can improve the efficacy of polycation-mediated siRNA delivery. Molecular Therapy-Nucleic Acids. 2018; 12: 207-219.

3. Riley RS, Dang MN, Billingsley MM, Abraham B, Gundlach L, Day ES. Evaluating the mechanisms of light-triggered siRNA release from nanoshells for temporal control over gene regulation. Nano Letters. 201818(6): 3565-3570.

4. Goyal R, Kapadia CH, Melamed JR, Riley RS, Day ES. Layer-by-layer assembled gold nanoshells for the intracellular delivery of miR-34a. Cellular and Molecular Bioengineering. 2018; 11(5): 383-396. 2018 Young Innovator Award in Cellular and Molecular Bioengineering.

5. Riley RS, Day ES. Frizzled7 antibody-functionalized nanoshells enable multivalent binding for Wnt signaling inhibition in triple negative breast cancer cells. Small. 2017; 13(26): 1700544.

6. Kouri FM, Hurley, LA, Daniel WL, Day ES, Hua Y, Peng C-Y, Queisser MA, Hao L, Merkel TJ, Ritner C, Zhang H, James CD, Sznajder JI, Chin L, Giljohann DA, Kessler JA, Peter ME, Mirkin CA, Stegh AH. miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma. Genes & Development. 2015; 29(7): 732-745. Featured cover article.

7. Jensen SA*, Day ES*, Ko CH*, Hurley LA, Luciano JP, Kouri FM, Merkel TJ, Luthi AJ, Patel PC, Cutler JI, Daniel WL, Scott AW, Rotz MW, Meade TJ, Giljohann DA, Mirkin CA, Stegh AH. Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma. Science Translational Medicine. 2013; 5(209): 209ra152. *co-first authors. Featured cover article.