Dual-liganded protein nanoparticles displaying TRAILs and EGFR binding affibodies enhance therapeutic efficacy against EGFR overexpressing triple negative breast cancers

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive and difficult-to-treat cancer that lacks expression of estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2). Due to the absence of these receptors, standard hormonal therapy and targeted therapy with HER2 are not effective for TNBC. Therefore, there is an urgent need for the development of TNBC-specific therapies. TNBCs often highly express the epidermal growth factor receptor (EGFR), which makes it an attractive target for TNBC treatment. Herein, we constructed a protein nanoparticle that polyvalently displays the cancer-specific apoptotic protein TNF-related apoptosis-inducing ligands (TRAILs) and EGFR-binding affibodies on a lumazine synthase protein nanoparticle (AaLS/TRAIL/EGFRAfb) and evaluated its therapeutic efficacy against EGFR-overexpressing TNBCs. AaLS/TRAIL/EGFRAfb tightly binds to the surface of TNBC cells, allowing for frequent and consistent interactions between TRAIL molecules on the protein cage and death receptors on TNBC cells, ultimately resulting in effective apoptotic cell death and tumor growth suppression. AaLS/TRAIL/EGFRAfb is a promising candidate for further development as a targeted therapeutic agent for TNBC treatment. This research highlights the potential of protein nanoparticle technology to develop new, effective, and targeted cancer therapies.