Tunable Linkers for Dynamic Thiol-Based Bioconjugation Strategies

Recent advancements in bioconjugation chemistry have increasingly focused on thiol-based strategies, offering reversible and stimuli-responsive mechanisms, particularly suited for biomedical applications. This review aims to provide a critical overview of the latest developments in thiol-containing linkers, such as disulfide bonds and photocleavable groups, emphasizing their role in enabling controllable and often reversible conjugation of biomolecules. The review will explore several applications, including peptide synthesis and peptide-stapling strategies, antibody–drug conjugates (ADCs), and responsive biomaterials, categorize key classes of cleavable thiol-based linkers, and analyze their mechanisms. Covering the literature from the past 15 years, focusing on innovations until 2024, this review addresses the chemical foundations and practical implementations of these systems, identifying current limitations and proposing future directions for designing selective, biocompatible, and functionally dynamic conjugation platforms.