Redox‐Regulated Phase Switchable Peptide Droplets with Degradation Resistance for Intravenous Delivery of Biopharmaceuticals

ABSTRACT Liquid‐liquid phase separation (LLPS) plays a ubiquitous and vital role during the formation of biomolecular coacervates, and the switchable phase transition between liquid and solid of these coacervates is crucial for a series of dynamic biochemical functions. Currently, tremendous work has been focused on constructing artificial coacervates using synthetic biomolecules; however, such a phase switch has not been achieved. Here, we demonstrate that by designing peptide sequences to match specific in vivo microenvironments, it is practical to utilize redox reactions to control the phase switch of peptide coacervates. Upon optimizing the chemical structure and concentration of peptide, as well as pH and temperature, both phase‐separation and phase‐transition dynamics could be finely regulated. Cyclically, liquid‐like membraneless coacervates are oxidized into solid‐like semipermeable coacervate vesicles, and return to liquid‐like membraneless coacervates under reductive microenvironments. Furthermore, animal experiments confirmed that oxidized solid‐like coacervate vesicles are able to remain stable against degradation during intravenous administration. Upon arriving at the reductive tumor site, solid‐like coacervate vesicles gradually become liquid‐like coacervate to promote intracellular siRNA delivery with significant inhibition effects against pancreatic tumor, which could pave the way for a new front of manipulating biomolecular LLPS for delivery of biopharmaceuticals.