Facile synthesis of redox-responsive peptide coacervates for cytosolic protein delivery

Histidine-rich peptide (HBpep) coacervates are promising intracellular delivery vehicles due to their excellent cellular uptake. However, cargo release usually relies on redox-responsive motifs linked to lysine side chains via multi-step and complex organic reactions. Here, we report a new design that directly introduces a disulfide bond into the phase-separating peptide backbone to simplify synthesis. This disulfide bond is cleaved in the reducing cytosol, producing two short peptide fragments that trigger coacervate disassembly and cargo release. A series of peptide derivatives were synthesized, and peptide derivative 6 showed optimal delivery performance, efficiently delivering eGFP and various other proteins into multiple cell lines. This strategy not only simplifies synthesis but also provides a more convenient and cost-effective disassembly mechanism for coacervate-based biomolecule delivery.