Legumain-Triggered Biomolecular Condensates for Intracellular Delivery of Peptidomimetics for Anticancer Application

Objective

Intracellular delivery of unmodified therapeutic peptides remains a major challenge in targeted cancer therapy, due to poor cell permeability and rapid degradation. This fellowship addresses that limitation by developing enzyme-triggered biomolecular condensates (BMCs) as a spatiotemporally controlled delivery platform for cancer-relevant protein–protein interaction (PPI) inhibitors. The model target is the TACC-3/Aurora-A mitotic complex, with additional PPIs including TPX-2/Aurora-A and BH3/BCL-2 family interactions to demonstrate broader applicability. I will design aggregation-induced emission (AIE)-tagged peptide scaffolds that self-assemble into BMCs incorporating bioactive peptidomimetics to enable real-time visualization of condensate formation and intracellular distribution. Upon cancer cell uptake, the tumor-associated protease legumain will induce condensate disassembly, releasing the peptidomimetics. Longer term, this offers promise to release the peptidomimetic precisely at a tumor site while minimizing off-target exposure. The strategy will preserve the peptidomimetics’ bioactivity and ensure selective mitotic disruption or apoptosis leading to cell death. Key objectives include the synthesis of peptide–peptidomimetic hybrids, characterization of their binding kinetics (using biophysical tools such as ITC and fluorescence anisotropy) and cellular uptake, and quantification of spindle disruption and apoptosis markers (using imaging). By integrating image-guided delivery with enzyme-responsive release, this project goes beyond the state of the art, enabling enzyme-triggered, spatiotemporal control of intracellular delivery of unmodified peptidomimetics while preserving their bioactivity and offering a novel avenue for therapeutic intervention. The aligned additional training activities needed to deliver the project objectives will simultaneously elevate my research competences and profile ready for a position as a group leader in industry or academia.