Elastin-Like Polypeptide Nanoparticles as Carriers for Anti-EGFR Peptide Therapeutics

Peptides have recently gained significant attention for their potential use as therapeutic drugs. However, several challenges hinder their pharmaceutical application, including high production costs, complex synthesis methods, and short in vivo half-lives. This project addresses these challenges by utilizing elastin-like polypeptides (ELPs) as a drug delivery vehicle, taking advantage of their biocompatibility and temperature-responsive self-assembly into micelles. We engineered a novel fusion protein that combines ELP with the Leucine-Rich Repeat 6 (LRR6) domain from human Decorin, which functions as an EGFR antagonist. This design effectively presents LRR6 in a way that preserves its ability to inhibit the epidermal growth factor receptor (EGFR), a receptor whose overexpression drives the growth of many cancers. Our engineered ELP-LRR6 (ELD6) fusion protein forms micelles at body temperature and achieves EGFR-targeted delivery while acting as the EGFR antagonist to kill tumor cells efficiently. In contrast, ELP micelles, as a control, fail to target EGFR and exert tumor cell-killing activity. By docking tools, we refined the LRR6 to a shorter fragment that maintains its ability to antagonize EGFR and identified the key amino acids within LRR6 responsible for binding to EGFR. Overall, this work demonstrates the efficiency of ELP micelle, improving both the targeting and bioactivity of peptide drugs like LRR6, representing a promising nanoparticle-based drug delivery system for peptide drugs. Additionally, by integrating molecular docking with experiments, we were able to accelerate the discovery and optimization of peptide drugs.