The Yes-associated protein (YAP) is a major oncoprotein responsible for cell proliferation control. YAP's oncogenic activity is regulated by both the Hippo kinase cascade and uniquely by a mechanical-force-induced actin remodeling process. Inspired by reports that ovarian cancer cells specifically accumulate the phosphatase protein ALPP on lipid rafts that physically link to actin cytoskeleton, we developed a molecular self-assembly (MSA) technology that selectively halts cancer cell proliferation by inactivating YAP. We designed a ruthenium-complex-peptide precursor molecule that, upon cleavage of phosphate groups, undergoes self-assembly to form nanostructures specifically on lipid rafts of ovarian cancer cells. The MSAs exert potent, cancer-cell-specific antiproliferative effects in multiple cancer cell lines and in mouse xenograft tumor models. Our work illustrates how basic biochemical insights can be exploited as the basis for a nanobiointerface fabrication technology which links nanoscale protein activities at specific subcellular locations to molecular biological activities to suppress cancer cell proliferation.

The precision and efficacy of photodynamic therapy (PDT) is essential for the treatment of brain tumors because the cancer cells are within or adjacent to the delicate nervous system. Taurine is an abundant amino acid in the brain that serves the central nervous system (CNS). A taurine-modified polypyridyl Ru-complex was shown to have optimized intracellular affinity in cancer cells through accumulation in lysosomes. Symmetrical modification of this Ru-complex by multiple taurine molecules enhanced the efficiency of molecular emission with boosted generation of reactive oxygen species. These characteristic features make the taurine-modified Ru-complex a potentially effective photosensitizer for PDT of target cancer cells, with outstanding efficacy in cancerous brain cells.

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.

Malignant brain cancer remains challenging in treatment due to the highly invasive quality of gliomas. Inspired by the upregulated expression of integrin β1 subunits in tumors, we designed and synthesized an integrin-targeting self-assembling ligand based on a laminin-derived peptide that selectively forms nanofibrous microdomains on the apical membrane of glioma cells, inhibiting their migration and invasion.

No abstract