Molecular engineering approaches to half-life extension of therapeutic biomolecules

Therapeutic biomolecules are widely used to treat various diseases, but their clinical efficacy is often limited by short in vivo half-lives due to rapid renal filtration, proteolytic degradation, and immune clearance. Short half-life leads to frequent dosing, fluctuation in blood drug concentration, and increased treatment costs, severely limiting clinical efficacy. To address these challenges, various half-life extension strategies have been developed, including chemical conjugation (e.g., PEGylation), physical delivery systems (e.g., microspheres), and genetic/fusion approaches. This review provides a comprehensive narrative analysis of molecular engineering methods, discussing the rational design to directly optimize the drug molecule itself or fuse it with long-acting carriers to significantly extend its circulation time. A systematic comparison of several approaches is presented to guide rational strategy selection. By synthesizing current knowledge and recent advances, this review serves as a practical resource for researchers and drug developers navigating half-life extension technologies.