Artificial protein scaffolds for human therapeutics: drug discovery and delivery strategies

Artificial protein scaffolds have emerged as next-generation biologics that address key limitations of monoclonal antibodies, including large size, poor tissue penetration and complex manufacturing. This review discusses major scaffold classes, including antibody-derived and non-antibody platforms, and highlights engineering strategies, such as rational design, library screening, AI-driven optimization and multi-specific formats. Their expanding roles in drug discovery, including target validation, hit identification, mechanistic studies and companion diagnostics, are examined alongside therapeutic applications in oncology, immunotherapy, infectious diseases, metabolic disorders and central nervous system (CNS) disorders. The article further outlines scaffold-enabled drug delivery strategies, conjugation approaches and clinical progress. Key translational challenges, such as immunogenicity, pharmacokinetics and manufacturing, are discussed, along with future opportunities to integrate artificial intelligence and precision medicine to advance scaffold-based therapeutics.