Heparan Sulfate-Instructed Self-Assembly Selectively Inhibits Cancer Cell Migration

Heparan sulfate (HS) has important emerging roles in oncogenesis, which represents potential therapeutic strategies for human cancers. However, due to the complexity of the HS signaling network, HS-targeted synthetic cancer therapeutics has never been successfully devised. To conquer the challenge, we developed HS-instructed self-assembling peptides by decorating the “Cardin–Weintraub” sequence with aromatic amino acids. The HS-binding interactions induce localized accumulation of synthetic peptides triggering molecular self-assembly in the vicinity of highly expressed Heparan sulfate proteoglycans (HSPGs) on the cancer cell membrane. The nanostructures hinder the binding of HSPG with metastasis promoting protein–heparin-binding EGF-like growth factor (HBEGF) inhibiting the activation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). Our study proved that HS-instructed self-assembly is a promising synthetic therapeutic strategy for targeted cancer migration inhibition.