Single-Chain Variable Fragment Fusion Proteins for Targeted Delivery and Therapy

A single-chain variable fragment (scFv) is an engineered antibody derivative that retains antigen-binding specificity while having a much smaller size than an antibody, improved tissue penetration, and enhanced versatility for genetic manipulation. When an scFv is fused with diverse protein payloads, multifunctional biologics can be created for targeted delivery and therapy. Over the past decade, scFv fusion proteins have gained significant traction in oncology, where they have been incorporated into immunotoxins, immunocytokines, bispecific antibodies, Chimeric Antigen Receptor (CAR)-T cells constructs, and immune cell engagers. In addition, advances in blood-brain barrier (BBB)-targeting strategies have enabled the exploration of scFv-based therapeutics for neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Despite promising preclinical and clinical outcomes, challenges such as structural instability, short half-life, immunogenicity, and manufacturing complexity remain. This review provides an in-depth and up-to-date overview of scFv fusion protein engineering and its therapeutic applications in cancer and neurodegenerative disorders. We also highlight the clinical translations and design principles of scFv fusion proteins.