Journal ArticlePolyphenol-stabilized coacervates for enzyme-triggered drug deliveryYim, Wonjun; Jin, Zhicheng; Chang, Yu-Ci; Brambila, Carlos; Creyer, Matthew N; Ling, Chuxuan; He, Tengyu; Li, Yi; Retout, Maurice; Penny, William F; Zhou, Jiajing; Jokerst, Jesse V<title>Abstract</title> <p>Stability issues in membrane-free coacervates have been addressed with coating strategies, but these approaches often compromise the permeability of the coacervate. Here we report a facile approach to maintain both stability and permeability using tannic acid and then demonstrate the value of this approach in enzyme-triggered drug release. First, we develop size-tunable coacervates via self-assembly of heparin glycosaminoglycan with tyrosine and arginine-based peptides. A thrombin-recognition site within the peptide building block results in heparin release upon thrombin proteolysis. Notably, polyphenols are integrated within the nano-coacervates to improve stability in biofluids. Phenolic crosslinking at the liquid-liquid interface enables nano-coacervates to maintain exceptional structural integrity across various environments. We discover a pivotal polyphenol threshold for preserving enzymatic activity alongside enhanced stability. The disassembly rate of the nano-coacervates increases as a function of thrombin activity, thus preventing a coagulation cascade. This polyphenol-based approach not only improves stability but also opens the way for applications in biomedicine, protease sensing, and bio-responsive drug delivery.</p>Springer Nature2024-12-0110572707Nature Communications1512041-1723https://doi.org/10.1038/s41467-024-51218-82242375National Science Foundation