Long-circulating protein-polymer conjugates: Advancing beyond PEGylated proteins

Protein-polymer conjugation has emerged as a powerful approach to prolong the in vivo half-life of therapeutic proteins, enabling reduced administration frequency and improved patient compliance. Among various conjugation methods, PEGylation has become the most successful strategy for more than 34 clinically approved drugs and have established the gold standard for long-acting biotherapeutics. Over the past decades, continuous advances in polymer chemistry and conjugation technologies have driven the innovation of alternatives to polyethylene glycol (PEG) to overcome its inherent limitations, such as non-biodegradability, limited functionality, and potential immunogenicity. In this review, we summarize the development and recent progress of long-circulating protein-polymer conjugates beyond PEGylation, focusing on emerging PEG alternatives, key design principles such as size expansion, shape modulation, controlled release, active targeting, and immunomodulation. Furthermore, the current challenges in large-scale manufacture, quality control, and clinical translation are discussed. This review provides insights into the emerging directions for next-generation long-circulating conjugates and charts a rational path toward the design of more effective long-acting therapeutics.