Gene Regulation

RNA Interference Antibody-Mediated Signal Cascade Interference

One way the Day Lab enables high precision therapy is by designing nanoparticles to deliver antagonistic RNA molecules or antibodies to suppress the expression of disease-promoting genes. 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. Hoover EC, Day ES. Antibody/siRNA nanocarriers against Wnt signaling suppress oncogenic and stemlike behavior in triple-negative breast cancer cells. Journal of Biomedical Materials Research Part A. 2025; 113(1): e37867.
  2. Hoover EC, Roy Chowdhury C, Ruggiero OM, Day ES. Conjugation of antibodies and siRNA duplexes to polymer nanoparticles via maleimide-thiol chemistry. ACS Omega. 2024; 9(48): 47637-47646.
  3. Dang MN, Suri S, Li K, Gomez Casas C, Stigliano G, Riley RS, Scully MA, Hoover EC, Aboeleneen SB, Kramarenko GC, Day ES. Antibody and siRNA nanocarriers to suppress Wnt signaling, tumor growth, and lung metastasis in triple-negative breast cancer. Advanced Therapeutics. 2024; 7(6): 2300426.
  4. Scully MA, Wilhelm R, Wilkins DE, Day ES. Membrane-cloaked nanoparticles for RNA interference of β-catenin in triple-negative breast cancer. ACS Biomaterials Science & Engineering. 2024; 10(3): 1355-1363
  5. Fereshteh Z, Dang MN, Wenck C, Day ES, Slater JH. E-selectin targeted gold nanoshells to inhibit breast cancer cell binding to lung endothelial cells. ACS Applied Nano Materials. 2023; 6(2): 1315-1324.
  6. Dang MN, Gomez Casas C, Day ES. Photoresponsive miR-34a/nanoshell conjugates enable light-triggered gene regulation to impair the function of triple-negative breast cancer cells. Nano Letters. 2021; 21(1): 68-76.
  7. Valcourt DM, Day ES. Dual regulation of miR-34a and Notch signaling in triple-negative breast cancer by antibody/miRNA nanocarriers. Molecular Therapy-Nucleic Acids. 2020; 21; 290-298.
  8. Wang J, Dang MN, Day ES. Inhibition of Wnt signaling by Frizzled7 antibody-coated nanoshells sensitizes triple-negative breast cancer cells to the autophagy regulator chloroquine. Nano Research. 2020; 13: 1693–1703.
  9. Valcourt DM, Dang MN, Scully MA, Day ES. Nanoparticle-mediated co-delivery of Notch-1 antibodies and ABT-737 as a potent treatment strategy for triple-negative breast cancer. ACS Nano. 2020; 14(3): 3378-3388.
  10. Kapadia CH, Ioele SA, Day ES. Layer-by-layer assembled PLGA nanoparticles carrying miR-34a cargo inhibit the proliferation and cell cycle progression of triple-negative breast cancer cells. Journal of Biomedical Materials Research Part A. 2020; 108A: 601-603.
  11. 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.
  12. 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.
  13. 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. 2018; 18(6): 3565-3570.
  14. 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. 
  15. 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.