Cell-penetrating antibody enhances nuclear delivery of triplex-forming oligonucleotides targeting HER2-positive cancers

Nucleic acid therapies (NATs) such as triplex-forming oligonucleotides (TFOs) offer innovative cancer treatment options to selectively target amplified oncogenes, such as <i>HER2</i>. However, challenges in intracellular and nuclear delivery hinder their clinical translation. Here, we explore the use of a lupus-derived anti-DNA monoclonal antibody, 3E10, as a delivery system for <i>HER2</i>-targeted TFOs. 3E10, which naturally localizes to tumors by binding extracellular DNA in necrotic regions, effectively transports TFOs into the nucleus. Moreover, the D31N mutant of 3E10 demonstrated superior binding and delivery efficiency in both <i>in vitro</i> and <i>in vivo</i> HER2-positive breast cancer models. These results establish a promising platform for TFO-based precision cancer therapies, leveraging the tumor-targeting properties of 3E10 to enhance bioavailability.