Dynamic Polymer Amphiphiles for Efficient Intracellular and In Vivo Protein Delivery

Abstract Intracellular delivery of proteins is receiving considerable attention in biotherapeutics for various diseases by replacing dysfunctional proteins. Successful intracellular protein delivery highly relies on the development of efficient and safe polymeric carriers, which remains a grand challenge due to the lack of strong binding sites on proteins and their distinct molecular sizes and polarities. In this work, a strategy is proposed for efficient intracellular protein delivery by using dynamic polymer supra‐amphiphiles, which are prepared by grafting boronated polylysine with a series of lipidated catechols via dynamic covalent catechol–boronate ester bonds. The prepared supra‐amphiphiles can coassemble with proteins to form stable nanoparticles in water and also enable the release of bound proteins in cells due to their dynamic features, thereby strongly promoting the intracellular delivery process. The lead supra‐amphiphiles screened in the library demonstrate high efficiency in the delivery of various proteins including bovine serum albumin, β‐galactosidase, α‐chymotrypsin, saporin, R‐phycoerythrin, ovalbumin, catalase, and superoxide dismutase, and show great potency in delivering superoxide dismutase to treat ulcerative colitis in vivo. This work provides new opportunities for rational design and facile construction of robust intracellular protein delivery materials by the integration of polymer chemistry and supramolecular engineering strategies.