Manipulating Cell Fates with Protein Conjugates

The homeostasis of cellular activities is essential for the normal functioning of living organisms. Hence, the ability to regulate the fates of cells is of great significance for both fundamental chemical biology studies and therapeutic development. Despite the notable success of small-molecule drugs that normally act on cellular protein functions, current clinical challenges have highlighted the use of macromolecules to tune cell function for improved therapeutic outcomes. As a class of hybrid biomacromolecules gaining rapidly increasing attention, protein conjugates have exhibited great potential as versatile tools to manipulate cell function for therapeutic applications, including cancer treatment, tissue engineering, and regenerative medicine. Therefore, recent progress in the design and assembly of protein conjugates used to regulate cell function is discussed in this review. The protein conjugates covered here are classified into three different categories based on their mechanisms of action and relevant applications: (1) regulation of intercellular interactions; (2) intervention in intracellular biological pathways; (3) termination of cell proliferation. Within each genre, a variety of protein conjugate scaffolds are discussed, which contain a diverse array of grafted molecules, such as lipids, oligonucleotides, synthetic polymers, and small molecules, with an emphasis on their conjugation methodologies and potential biomedical applications. While the current generation of protein conjugates is focused largely on delivery, the next generation is expected to address issues of site-specific conjugation, in vivo stability, controllability, target selectivity, and biocompatibility.