Redox-responsive peptide-based complex coacervates as delivery vehicles with controlled release of proteinous drugs

Dynamic recruitment and releasing of specific intracellular proteins in active membraneless organelles formed by liquid-liquid phase separation is an emerging path for regulation of many intracellular tasks. However, how such dynamic phase separation process have impacts on the efficiency of proteinous drugs is still not well understood. Herein, we present a novel design of complex coacervates as in vitro MLOs models, made from small metabolites anionic molecules and simple arginine-rich peptides a cationic motif through LLPS. These complex coacervates show the assembly and disassembly behavior can be regulated by redox chemistry in three pathways, that help to control the releasing of therapeutic protein. A model proteinous drugs tissue plasminogen activator (tPA) can rapidly compartmentalize inside the complex coacervates, and coacervates formed from peptide conjugated with RGD motif mimic fibrinogen binding to activated platelets show selective binding to the thrombus site and thus enhance on-target efficacy of tPA. Then the burst release of tPA can be controlled by the redox-induced dissolution of coacervates. Our proof-of-principle complex coacervate system provide insights into the sequestration and release of proteinous drugs from advanced drug delivery system that could be central to the MLOs in living cells.