Polymer conjugation benefits proteins beyond simply extended half-life

Polymer conjugation is well known to extend the half-life of proteins in the bloodstream. The resulting protein-polymer conjugates have gained tremendous success due to this benefit, most prominently with the numerous PEGylated protein therapeutics that have been approved by the Food and Drug Administration (FDA). Prolonged half-life of protein therapeutics is usually accompanied by improved therapeutic outcome and patient compliance. However, simply extending the half-life of proteins is no longer sufficient to address the different therapeutic requirements of different diseases. Modern medicine has placed higher functional demands for protein therapeutics, such as biological barrier permeability, lower off-target effects, and higher biosafety. Indeed, the benefits of polymer conjugation for proteins have been greatly expanded beyond just extending the half-life, such as improving therapeutic index, facilitating intracellular delivery, remodeling biodistribution, penetrating the blood-brain barrier, and promoting oral absorption. Therefore, this short review will aim to systematically reveal the benefits of polymer conjugation for proteins at molecular, nanoscale, cellular, tissue, organ, and organ system level. The challenge and new direction for the development and clinical translation of protein-polymer conjugates are also covered. STATEMENT OF SIGNIFICANCE: Since the concept was pioneered by Frank Davis in the late 1960s, protein-polymer conjugates have gained tremendous success. Therapeutics based on protein-polymer conjugates have longer half-lives in the bloodstream compared to their native forms, which reduces dosing frequency and greatly enhances patient compliance. Indeed, beyond improved pharmacokinetic, protein-polymer conjugates have demonstrated multifaceted biological benefits, such as facilitating intracellular delivery, penetrating tissue barriers, remodeling biodistribution, and promoting oral absorption. This review aims to systematically reveal the benefits of polymer conjugation for proteins at the molecular, nanoscale, cellular, tissue, organ, and organ system level. Such comprehensive understanding will not only broaden the impact of protein-polymer conjugates, but also enable researchers to advance their development in the desired direction.