Catalyst-free thiazolidine formation chemistry enables the facile construction of peptide/protein–cell conjugates (PCCs) at physiological pH

Although numerous genetic, chemical, and physical strategies have been developed to remodel the cell surface landscape for basic research and the development of live cell-based therapeutics, new chemical modification strategies capable of decorating cells with various genetically/non-genetically encodable molecules are still urgently needed. Herein, we describe a remarkably simple and robust chemical strategy for cell surface modifications by revisiting the classical thiazolidine formation chemistry. Cell surfaces harbouring aldehydes can be chemoselectively conjugated with molecules containing a 1,2-aminothiol moiety at physiological pH without the need to use any toxic catalysts and complicated chemical synthesis. Through the combined use of thiazolidine formation and the SpyCatcher–SpyTag system, we have further developed a SpyCatcher–SpyTag Chemistry Assisted Cell Surface Engineering (SpyCASE) platform, providing a modular approach for the construction of large protein–cell conjugates (PCCs) in their native state. Thiazolidine-bridged molecules can also be detached from the surface again through a biocompatible Pd-catalyzed bond scission reaction, enabling reversible modification of living cell surfaces. In addition, this approach allows us to modulate specific cell–cell interactions and generate NK cell-based PCCs to selectively target/kill several EGFR-positive cancer cells in vitro. Overall, this study provides an underappreciated but useful chemical tool to decorate cells with tailor-made functionalities.