Enzyme Induced Solid-like Condensates Formation of Engineered Peptide in Living Cells for Prostate Cancer Inhibition.

作者：Huaimin Wang, Ying Li, Tengyan Xu, Yaoting Li · 发表于：Angewandte Chemie · 年份：2025 · DOI：10.1002/anie.202504958 · 被引用次数：12 · 研究领域：Medicine

This work describes the rational design and synthesis of Hepsin-recognized amphiphilic branched peptides (DMN-SIPL) that can form solid condensates through liquid-liquid phase separation (LLPS) upon enzymatic reaction. The peptide forms solid-like condensates both in vitro and in living cells, triggered by type-II membrane-associated serine peptidase, Hepsin, whose overexpression determines prostate cancer progression. Specifically, integrating self-assembly, Hepsin hydrolysis, and Hepsin binding domain generates a branched substrate that acts a precursor for enzyme induced LLPS. Upon binding Hepsin on the cell membrane, DMN-SIPL forms condensates initiated by Hepsin induced self-assembly. The prostate cancer cells then uptake these condensates via lipid raft-mediated endocytosis. The entrapped Hepsin in the condensates further hydrolyze the DMN-SIPL to stabilize the intracellular condensates. Structure activity relationship reveals the importance of enzyme binding motif, enzyme recognized motif, and the self-assembly motif. Mechanistic studies indicate that the resulting solid-like condensates modulate cancer cell metabolism by inhibiting Hepsin upstream protein activation and downstream signal transduction, ultimately inducing cancer cell growth inhibition selectively. As a first example, this work investigates enzymatic LLPS condensates formation in living cells, paving the way to generate functional synthetic biomolecular condensates through LLPS for biomedical applicatio...