Generational shifts in thiolated cyclodextrins: Toward more efficient drug delivery systems

Thiolated cyclodextrins represent a rapidly evolving class of multifunctional excipients that extend the role of cyclodextrins beyond solubilization toward active participation in mucosal drug delivery. By integrating the inclusion complexation capacity of cyclodextrins with the reactivity of thiol groups, these systems can enhance drug residence time on target tissues, epithelial permeation, and cellular uptake. This review discusses the generational evolution of thiolated cyclodextrins, from first-generation derivatives bearing free sulfhydryl groups to advanced S-protected systems designed to improve stability, control reactivity, and enable deeper mucus penetration. Particular emphasis is placed on how second- and third-generation thiolated cyclodextrins overcome key limitations of conventional thiomers, including premature oxidation and superficial binding to the rapidly cleared mucus layer. We further highlight their emerging role as performance-enhancing excipients in oral, ocular, respiratory, and other mucosal delivery platforms, such as nanocarrier systems. By linking structural modification, mucoadhesion, mucus penetration, and absorption-enhancing mechanisms, this review provides a forward-looking perspective on thiolated cyclodextrins as next-generation tools for designing more efficient and biologically responsive drug delivery systems.