Polymer Chemistry in Living Cells

[Image: see text] The polymerization of biomolecules is a central operation in biology that connects molecular signals with proliferative and information-rich events in cells. As molecules arrange precisely across 3-D space, they create new functional capabilities such as catalysis and transport highways and exhibit new phase separation phenomena that fuel nonequilibrium dynamics in cells. Hence, the observed polymer chemistry manifests itself as a molecular basis leading to cellular phenotypes, expressed as a multitude of hierarchical structures found in cell biology. Although many milestone discoveries had accompanied the rise of the synthetic polymer era, fundamental studies were realized within a closed, pristine environment and that their behavior in a complex multicomponent system remains challenging and thus unexplored. From this perspective, there is a rich trove of undiscovered knowledge that awaits the polymer science community that can revolutionize understanding in the interactive nanoscale world of the living cell. In this Account, we discuss the strategies that have enabled synthetic polymer chemistry to be conducted within the cells (membrane inclusive) and to establish monomer design principles that offer spatiotemporal control of the polymerization. As reaction considerations such as monomer concentration, polymer growth dynamics, and reactivities are intertwined with the subcellular environment and transport processes, we first provide a chemical narrative of each major cellular compartment. The conditions within each compartment will therefore set the boundaries on the type of polymer chemistry that can be conducted. Both covalent and supramolecular polymerization concepts are explored separately in the context of scaffold design, polymerization mechanism, and activation. To facilitate transport into a localized subcellular space, we show that monomers can be reversibly modified by targeting groups or stimulus-responsive motifs that react within the specific compartment. Upon polymerization, we discuss the characterization of the resultant polymeric structures and how these phase-separated structures would impact biological processes such as cell cycle, metabolism, and apoptosis. As we begin to integrate cellular biochemistry with in situ polymer science, we identify landmark challenges and technological hurdles that, when overcome, would lead to invaluable discoveries in macromolecular therapeutics and biology.