Liquid-liquid phase separation-driven coacervate-derived hydrogels and their biological applications

Coacervation phenomena in the biological world can be categorized as intracellular and extracellular coacervation. Intracellular coacervation has inspired the formation of membrane-free coacervate droplets and the development of droplet-based drug delivery systems, whereas the extracellular coacervation observed in marine mussels has motivated the creation of numerous coacervate-derived hydrogels. Coacervate-derived hydrogels, formed via liquid-liquid phase separation and subsequent gelation, represent a promising class of biomaterials, particularly for advanced drug delivery. Given the current lack of systematic reviews on coacervate-derived hydrogels, this review systematically elucidated their formation mechanism, characterization techniques, material systems (including natural/synthetic polymers, peptides, and inorganic components), and diverse forms (e.g., injectable, powder-based, stimuli-responsive). We particularly highlighted their exceptional potential in drug delivery, leveraging their high loading capacity, gentle encapsulation that preserves bioactivity, and tunable release kinetics in response to physiological stimuli. Beyond drug delivery, we also discussed their broad applications in bioadhesives, tissue engineering, 3D printing, and artificial tissue construction. Furthermore, this review discussed the current challenges faced by coacervate-derived hydrogels, including in vivo stability, precise control over drug release, long-term biosafety, and clinical translation. It also provided perspectives on future research directions, aiming to promote the further development and application of these materials in precision medicine and regenerative medicine.