Targeted disruption of the BCL9/β-catenin interaction by endosomal-escapable nanoparticles functionalized with an E-cadherin-derived peptide.

Abnormal activation of the Wnt/β-catenin signaling pathway, which underlies multiple malignancies, promotes tumor progression; drugs that can block this pathway are therefore highly attractive candidates for anticancer therapy. Using a therapeutic peptide derived from E-cadherin region V (cECRV), we sought to develop a potent and selective antagonist of β-catenin that can disrupt the carcinogenic interaction between β-catenin and BCL9. More importantly, to overcome the pharmacological obstacles of peptide-derived therapeutics (poor nuclease stability and low membrane permeability), a gold nanoparticle (AuNP)-based nanocarrier was designed to deliver cECRV into the cytoplasm to modulate the intracellular interaction of β-catenin and BCL9. The resultant nanoparticle, pAuNP-cECRV, showed no cytotoxicity towards normal peripheral blood mononuclear cells and induced cycle arrest and subsequent apoptosis of Wnt-hyperactive cancer cells by antagonizing β-catenin to inhibit the Wnt pathway. Our results indicate that pAuNP-cECRV is very promising for application as an efficient and safe peptide delivery vector for cancer therapy.