Artificial lipidation of proteins and peptides: from mechanism to clinical applications

The landscape of modern medicine has been transformed by protein-based therapeutics, offering targeted treatments for complex disorders with remarkable specificity and efficacy. However, these biologics face significant limitations in clinical settings, including rapid clearance, vulnerability to enzymatic degradation, poor absorption across biological membranes and inefficient distribution within target tissues. Artificial lipidation provides an innovative solution to these challenges, by the deliberate attachment of lipid groups to proteins and peptide structures. This biomimetic approach harnesses principles observed in natural post-translational modifications to create therapeutics with superior pharmacological profiles. By strategically incorporating lipid moieties, researchers can significantly prolong circulation half-life through albumin binding, protect against proteolytic breakdown, facilitate cellular uptake, customize pharmacokinetic parameters and enhance tissue-specific targeting. This Review provides a comprehensive analysis of current lipidation technologies, contrasting covalent modification strategies with noncovalent complexation approaches. We examine the molecular mechanisms underlying the therapeutic benefits, survey successful clinical applications and explore emerging opportunities across diverse therapeutic areas. Through this analysis, we offer insights to guide rational design decisions for developing optimized lipidated biotherapeutics with enhanced clinical performance.