Vacuolated coacervate mediates the bimodal release kinetics of diverse macromolecular drugs in vivo

Developing a generalizable delivery system for mediating the multimode release kinetics of diverse macromolecular drugs of varying attributes is highly desired for treating various diseases. We utilized a vacuolated coacervate, in which a dense coacervate matrix functions as a molecularly crowded barrier to regulate the release rate of macromolecules preloaded in the vacuoles. The transient disruption of the coacervate matrix by ultrasound can open the vacuoles to trigger burst release of macromolecular cargoes both in vitro and in vivo, while the liquidity of the nanoparticle-assembled coacervate (named NPA coacervate hereafter) enables the coacervate matrix to be quickly recovered in seconds upon pausing ultrasound, restoring long-term linear release of macromolecules segregated within the vacuoles. Considering the liquid and water-immiscible nature of coacervates, we believe that the concept of a “vacuolated coacervate-based macromolecular reservoir” to regulate macromolecular release kinetics can be highly instrumental in the treatment of diverse diseases.