Targeted cancer therapy using protein nanoparticles dual-displaying TRAIL and cancer-targeting ligands

Abstract

The TNF-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent due to its ability to selectively binds to pro-apoptotic death receptors, which are frequently overexpressed in a wide range of cancer cells, thereby inducing strong apoptosis. However, the therapeutic benefit of TRAIL is limited by its short circulation half-life and poor accumulation at tumor site. To address these challenges, this study presents a targeted therapeutic platform based on protein cage nanoparticles that dual-display TRAIL and cancer-specific ligands. Using the SpyCatcher/SpyTag (SC/ST) ligation system, TRAIL and targeting ligands were successfully displayed on the surface of Aquifex aeolicus lumazine synthase (AaLS) nanoparticles. Surface display of TRAIL mimics the membrane-bound form of TRAIL and improves its in vivo stability. Furthermore, dual-display of cancer targeting ligands enables specific strong binding to cancer cells and significantly enhances TRAIL-mediated apoptosis compared to soluble TRAIL. Affibodies and nanobodies were employed as cancer cell-targeting ligands, selected based on the overexpression of specific cancer-associated surface markers. Strong therapeutic efficacy was demonstrated across various cancer cell types, including EGFR-overexpressing adenocarcinoma, CD13-overexpressing acute myeloid leukemia (AML), and triple-negative- breast cancer (TNBC). By tailoring ligand selection to each cancer type, this platform demonstrates versatile and potent anticancer activity. Overall, this strategy highlights the potential of modular protein nanoparticle systems for targeted cancer therapy through strategically combining cancer-specific targeting ligands with apoptosis inducing effector molecules in a cancer type-specific manner.