Reversible Click Chemistry for Ultrafast and Quantitative Formation of Protein-Polymer Nanoassembly and Intracellular Protein Delivery

Construction of polymer-protein nanoassemblies is a challenge as reactions between macromolecules, especially those involving proteins, are inherently inefficient due to the sparse reactive functional groups and low concentration requirements. We address this challenge using an ultrafast and reversible click reaction, which forms the basis for a covalent self-assembly strategy between side-chain functionalized polymers and surface-modified proteins. The linkers in the assembly have been programmed to release the incarcerated proteins in its native form, only when subjected to the presence of a specific trigger. The generality and the versatility of the approach have been demonstrated by showing that this strategy can be used for proteins of different sizes and isoelectric points. Moreover, simple modifications in the linker chemistry offers the ability to trigger these assemblies with various chemical inputs. Efficient formation of nanoassemblies based on polymer-protein conjugates has implications in a variety of areas at the interface of chemistry with materials and biology, such as in the generation of active surfaces and in delivery of biologics. As a demonstration of utility in the latter, we have shown that these conjugates can be used to transport functional proteins across cellular membranes.