Dual Regulation of miR-34a and Notch Signaling in Triple-Negative Breast Cancer by Antibody/miRNA Nanocarriers

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks expression of the three most common receptors present on other subtypes, leaving it unsusceptible to current targeted or hormonal therapies. In this study, we introduce an alternative treatment strategy for TNBC that exploits its overexpression of Notch1 receptors and its underexpression of the tumor suppressive microRNA (miRNA) miR34a. Studies have shown that introducing mimics of miR-34a to TNBC cells effectively inhibits cancer growth, but miR-34a cannot be administered in the clinic without a carrier. To enable delivery of miR-34a to TNBC cells, we encapsulated miR-34a mimics in poly(lactic-co-glycolic acid) nanoparticles (NPs) that were functionalized with Notch1 antibodies to produce N1-34a-NPs. In addition to binding Notch1 receptors overexpressed on the surface of TNBC cells, the antibodies in this formulation enable suppression of Notch signaling through signal cascade interference. Herein, we present the results of in vitro experiments that demonstrate N1-34a-NPs can regulate Notch signaling and downstream miR-34a targets in TNBC cells to induce senescence and reduce cell proliferation and migration. These studies demonstrate that NP-mediated co-delivery of miR-34a and Notch1 antibodies is a promising alternative treatment strategy for TNBC, warranting further optimization and in vivo investigation in future studies.