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.

开发一种通用的递送系统来介导不同属性的多种大分子药物的多模式释放动力学对于治疗各种疾病是非常需要的。我们利用空泡凝聚层，其中致密凝聚层基质充当分子拥挤屏障来调节释放速率预装在液泡中的大分子。超声对凝聚层基质的短暂破坏可以打开液泡，从而在体外和体内触发大分子货物的爆发释放，而纳米颗粒组装的凝聚层（以下称为NPA凝聚层）的流动性使凝聚层基质能够快速恢复暂停超声波后几秒钟内，恢复液泡内分离的大分子的长期线性释放。考虑到凝聚层的液体和水不混溶性质，我们相信“基于空泡凝聚层的大分子储库”的概念来调节大分子释放动力学对于治疗多种疾病非常有帮助。