Boronate Building Blocks for Intracellular Protein Delivery

Intracellular protein delivery plays a critical role in the development of biotherapeutics and biotechnologies, yet it is hampered by a number of factors including protein binding, cellular uptake, endosomal escape, and protein release. Boronate building blocks, which are frequently employed to create effective protein delivery systems, have shown significant promise in overcoming these limitations thanks to their versatile reactivities and stimuli-responsive property. Boronate ligands transport conjugated proteins into the cytosol via receptor-mediated endocytosis by forming reversible boronate disaster bonds with carbohydrates like sialic acid on the cell surface. Additionally, boronate modification gives cargo proteins extra binding sites for forming complexes with nanocarriers. After internalization, boronate-tagged proteins are released from their carriers in response to endolysosomal acidity, reactive oxygen species, and adenosine triphosphate, and sometimes transport into the nucleus via the importin α/β pathway. Besides, boronate ligands are directly decorated on nanocarriers to enhance their binding affinity to native proteins via nitrogen–boron coordination. Owing to these promising features, various supramolecular and dynamic nanoassemblies are constructed based on boronate building blocks for efficient intracellular protein delivery.