Thiolated polyethoxylated surfactants have emerged as functional excipients in advanced drug delivery systems due to their unique ability to form covalent disulfide bonds with cysteine-rich mucin subdomains. The introduction of thiol/sulfhydryl (-SH) groups onto the surfactant surface can enhance mucoadhesion and prolongs mucosal residence; however, these interactions are highly context-dependent, governed by factors such as the mucosal redox state, the pKa of the thiol groups, and the steric accessibility of mucin cysteine. This review provides a comprehensive overview of mucosal barriers and the fundamental principles of mucoadhesion, emphasizing the biochemical interactions between thiolated polyethoxylated surfactants and mucin glycoproteins. The chemistry, synthetic strategies, characterization techniques, and thiol quantification assays are systematically discussed to elucidate the structure–function relationship governing their performance. Furthermore, the review highlights the integration of thiolated surfactants into various lipid-based systems, including solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, and self-emulsifying drug delivery systems, with an emphasis on formulation design, mechanistic insights, and performance outcomes. Safety, biocompatibility, and regulatory considerations are critically examined to evaluate their translational readiness. Finally, the review identifies existing research gaps and future opportunities, underscoring thiolated polyethoxylated surfactants as a promising, biointeractive platform for advanced mucoadhesive and biointeractive drug delivery technologies. • Thiolated polyethoxylated surfactants introduce reactive surface sulfhydryl groups. • Covalent thiol–mucin bonding can enhance mucoadhesion and residence at mucosal sites. • Thiolation alters interfacial behavior, colloidal stability, and potential pathways for drug absorption. • Synthetic strategies and analytical methods for thiol quantification are critically outlined. • Integration into SLNs, NLCs, SEDDS and nanoemulsions offers the potential to improve drug bioavailability. • Regulatory, safety and biocompatibility challenges for clinical translation are examined.
Hashmi et al. (Sun,) studied this question.