Nano-Protomers Targeting Tumor Metastasis Using HER3-Directed Fusion Construct

Therapeutic failure in many highly aggressive cancers is often driven by early metastatic spread and poor delivery of effective treatments. Protein-based therapeutics represent an attractive alternative to small-molecule drugs due to their strong biological activity, target selectivity, and generally limited off-target effects. In this work, we investigated whether a HER3-directed fusion construct, HPK, can function as a carrier to transport three different protein payloads—GFP, Gelonin, and GJA1-20k—into HER3-positive tumor cells. By incorporating a simple tagging motif onto each cargo, we assessed HPK’s capacity to load the proteins, recognize HER3 on the tumor cell surface, and promote internal uptake. Our findings show that HPK engages HER3 with high specificity, mediates efficient entry into cancer cells, and delivers intact, functional protein therapeutics. In vivo studies using melanoma and triple-negative breast cancer (TNBC) models further demonstrate that HPK enables payload activity within tumors. Collectively, these results identify HPK as a promising vehicle for successful protein delivery and highlight its potential utility in treating HER3-expressing cancers. Citation Format: Rebecca Benhaghnazar, Dutsin Sirvinas, Joseph Aceves, Ryan Cho, Felix Alonso-Valenteen, Nelyda Gonzalez, Ravinder Abrol, Robin Shaw, Lali Medina-Kauwe. Nano-protomers targeted at tumor metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4551.