Bridging discovery and therapy in precision medicine-Phage display as a catalyst for nanobody innovation: A review

Monoclonal antibodies, particularly immunoglobulin G (IgG)-based formats, have shown significant efficacy in targeted therapies; however, they face limitations such as poor tissue penetration, complex manufacturing, and antigen escape. These limitations have driven the development of alternative therapeutic strategies, such as bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptor T cells, each with their own technical and translational challenges. Nanobodies (Nbs), derived from camelid heavy-chain-only antibodies, are the smallest functional antibody fragments and are gaining attention as next-generation therapeutics. Their small size, high stability, superior solubility, efficient tissue penetration, and ease of genetic manipulation make them well-suited for addressing limitations of conventional antibodies. The FDA approval of caplacizumab and ciltacabtagene autoleucel validates the clinical potential of Nb therapeutics. However, continued innovation in their discovery and development remains essential. This review focuses specifically on the role of phage display in the advancement of FDA-approved and clinical-stage Nb therapeutics as of April 2025. It highlights how the Nb format design affects their mechanism of action and therapeutic potential across various diseases. By summarizing recent developments and outlining future directions, this review highlights the transformative role of phage display-derived Nb therapeutics in precision medicine and the management of complex diseases.