Polypeptide-protein conjugation: A new paradigm for therapeutic protein delivery

Abstract

Protein therapeutics have emerged as a potent and highly targeted treatment for a wide range of diseases, including cancer, immune disorders, and genetic conditions. However, their clinical applications are often constrained by challenges such as low stability, short circulation half-life, immunogenic responses, and high manufacturing expenses. The rapid development of biodegradable and biocompatible polypeptide materials provides innovative strategies to address these limitations. In particular, polypeptide-protein conjugation, the covalent linkage of a polypeptide chain to therapeutic proteins, has emerged as a promising strategy for enhancing specific delivery of therapeutic proteins. Leveraging the unique properties of polypeptides, these conjugates significantly improve the stability, solubility, and bioavailability of therapeutic proteins, thereby enhancing their therapeutic efficacy and reducing side effects. This review comprehensively summarizes the recent progress in this field, discussing the current obstacles faced by therapeutic proteins in clinical applications, fundamental design principles, and methodologies for constructing well-defined polypeptide-protein conjugates. Key advancements discussed include innovations in polypeptide synthesis, protein modification, bioorthogonal reactions for precise conjugation, techniques for conjugate purification and characterization. The review further summarizes recent progresses of various polypeptide-protein conjugates for therapeutic protein delivery. Current obstacles and future research directions are also highlighted, underscoring the potential of polypeptide-protein conjugation to propel further advancement in therapeutic protein delivery.