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.
Chitosanases are attractive biocatalysts for producing bioactive chito-oligosaccharides (COS), but their applications are limited by insufficient catalytic efficiency, poor stability, and challenging recovery. Although many chitosanases can be activated by metal ions, the direct addition of free ions into reaction systems suffers from low efficiency and separation challenges. This study presented a MOF-based strategy to create a Cu-enriched coordination microenvironment, enabling simultaneous immobilization and activation of marine polysaccharide hydrolases. Taking chitosanase OUC-CsnCA as a model, the immobilization on Cu-trimesic acid (Cu-BTC) doubled its activity (413.5 ± 34.7 U/mg) and increased kcat from 361.8 ± 8.0 to 704.4 ± 16.1 min−1, along with improved thermostability and pH tolerance. MALDI-TOF-MS and HPLC confirmed deeper substrate depolymerization upon immobilization. Kinetic and spectroscopic analyses revealed that Cu2+-binding modulated enzyme conformation and promoted enzyme–substrate interactions. Molecular dynamics simulations further indicated that Cu2+ coordination was associated with adjustments in catalytic cleft geometry (D102–E84) and reinforcement of hydrogen-bond interactions within the substrate-binding pocket. Enhanced activities were further observed for immobilized ι-carrageenase and α-agarase, demonstrating the potential applicability of this strategy to other metal-responsive marine polysaccharide hydrolases.
Mulberry leaf is a traditional Chinese herbal medicine with hepatoprotective properties, but the role of its polysaccharides in counteracting drug-induced liver injury (DILI) remains unexplored. Herein, a polysaccharide named MBPS-02 A was isolated from mulberry leaves, which featured a backbone of 1,2-α-Rhap, 1,4-α-GalpA, 1,4-α-Galp and 1,6-β-Galp, with branches including 1,4-β-Galp, t-β-Galp, t-β-GlcpA, 1,5-α-Araf, t-α-Araf and t-α-GalpA. MBPS-02 A attenuated acetaminophen (APAP)-induced DILI in mice, as evidenced by reduced hepatic inflammatory damage and oxidative stress. Additionally, it strengthened intestinal barrier integrity and reshaped the gut microbiota, promoting Akkermansia proliferation both in vivo and in vitro. Correlation analysis identified the Akkermansia-derived tripeptide glycylprolylarginine (GPR) as a key metabolite strongly associated with DILI amelioration. Cellular experiments confirmed that GPR scavenges hydrogen peroxide and upregulates catalase expression in hepatocytes, thereby protecting liver cells. Collectively, these results suggest MBPS-02 A as a promising natural polysaccharide candidate for DILI intervention via the gut-liver axis, and provide mechanistic insights into the hepatoprotective use of mulberry leaves.
