Programmable Coacervates Based on Minimalist Sticker–Spacer Frameworks: Chemical Design, Functions, and Emerging Applications

Membraneless compartments, such as coacervates, have emerged as powerful biomimetic models of protocells and fundamental regulators of the spatiotemporal organization of biochemical processes in living systems. The sticker-spacer framework offers a reductionist yet predictive approach for understanding and programming liquid-liquid phase separation (LLPS). In this review, we critically examine how the chemical identity of stickers and the architecture of spacers govern phase behavior, emphasizing that precise molecular design is often essential to achieve well-defined coacervate morphologies and to unravel their underlying physicochemical principles. We highlight recent advances in both simple and complex coacervate formed through sticker-spacer frameworks, physical and chemical properties of sticker and spacers, in situ spacer formation, light-responsive assemblies, and transition of coacervate droplets into thermodynamically stable nano assemblies. Key examples of chemical reactions within coacervates and delivery of drugs and macromolecules using sticker-spacer-engineered coacervates as carriers are discussed. Finally, we present an outlook that underscores the versatility of designer sticker-spacer frameworks as a unifying strategy for constructing adaptive coacervate protocells with broad potential in biocatalysis and biomedical applications.