(SD2025-055) A SYNTHETIC BIOMOLECULAR CONDENSATE FOR ON-DEMAND ANTICOAGULATION: This material automatically releases the anticoagulant heparin when thrombin (clotting factor) levels get too high.

Abstract

Stability issues in membrane-free coacervates have been addressed with coating strategies, but these approaches often compromise the permeability of the coacervate. Researchers from UC San Diego have invented 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, the researchers developed 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. The UCSD scientists discovered 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. 

Technology Description

Researchers from UC San Diego developed a stable and enzyme-responsive coacervate platform. They first engineered a nano-sized coacervate made of bio-inspired peptides and the anticoagulant heparin. Heparin plays an important role in surgical and cardiovascular medicine due to its short half-life, reversible nature, and low cost. However, heparin is difficult to manage and requires blood draws and central labs, therefore, the controlled release of heparin via the enzymatic activity of clotting factors is gaining interest. Living organisms maintain hemostasis through precise molecular feedback regulations. For example, vascular injury triggers a coagulation cascade process where clotting factors activate prothrombin to thrombin, transforming fibrinogen into insoluble fibrin by cleavage. Together with platelet activation, this process produces stable fibrin clots to prevent excessive bleeding. The inventors envision that by incorporating a feedback loop system within the coacervates, they could regulate heparin release based on thrombin activity. Increasing environmental thrombin levels would promptly trigger heparin release, while normal physiological thrombin levels would leave the coacervates intact—thus, there would be no risk of excessive bleeding.

Applications

For example, vascular injury triggers a coagulation cascade process where clotting factors activate prothrombin to thrombin, transforming fibrinogen into insoluble fibrin by cleavage. Together with platelet activation, this process produces stable fibrin clots to prevent excessive bleeding. The inventors envision that by incorporating a feedback loop system within the coacervates, they could regulate heparin release based on thrombin activity. Increasing environmental thrombin levels would promptly trigger heparin release, while normal physiological thrombin levels would leave the coacervates intact—thus, there would be no risk of excessive bleeding.

Advantages

State Of Development

Intellectual Property Info

UC San Diego has international patent rights (patent-pending) available for commercial development.

Related Materials

• Yim W, Jin Z, Chang YC, Brambila C, Creyer MN, Ling C, He T, Li Y, Retout M, Penny WF, Zhou J, Jokerst JV. Polyphenol-stabilized coacervates for enzyme-triggered drug delivery. Nat Commun. 2024 Aug 24;15(1):7295. - 08/24/2024