Ultrahigh‐Affinity Molecular Recognition in Water and Biomedical Applications

Abstract Aqueous‐phase molecular recognition pairs with ultrahigh binding affinity hold immense value in biotechnology and chemical applications. However, the rational design of synthetic pairs with such exceptional binding strength has long remained a significant challenge, with notable progress achieved only in recent years. In this minireview, we begin by defining the term “ultrahigh‐affinity” through a comprehensive analysis of available data on aqueous‐phase molecular recognition by water‐soluble macrocyclic hosts. Based on this foundation, we provide a detailed overview of the latest advancements in various classes of ultrahigh‐affinity receptors, extracting key design principles that drive their remarkable performance. We further highlight emerging applications of ultrahigh‐affinity molecular pairs in biomedical materials, spanning bioorthogonal chemistry, biosensing, bioimaging, drug delivery, and toxin sequestration. These examples underscore the transformative potential of ultrahigh‐affinity recognition in addressing real‐world biomedical challenges. Finally, we offer a forward‐looking perspective on the future of this rapidly evolving field, exploring potential directions for designing more diverse and functional ultrahigh‐affinity molecular recognition tools. By bridging the gap between fundamental science and practical applications, this minireview aims to inspire the development of next‐generation molecular recognition systems and foster deeper integration between supramolecular chemistry and biomedical materials, paving the way for innovative solutions to pressing biomedical needs.