Redox responsive cyclodextrin-based drug delivery systems: a special insight to glutathione responsive CD-nanosponges

Advances in nanotechnology and nanomedicine increasingly focus on the rational design of smart nanocarriers capable of site-specific and stimulus-triggered drug release to improve therapeutic efficacy and reduce systemic toxicity. Among them, cyclodextrins (CDs), particularly cyclodextrin nanosponges (CDNSs), have emerged as safe, biodegradable, and versatile platforms for drug delivery due to favorable biocompatibility and structural adaptability.

CDNSs are three-dimensional, cross-linked polymeric networks formed through chemical reactions between cyclodextrins and suitable cross-linkers, generating porous architectures with high surface area and tunable physicochemical properties. These features enable efficient encapsulation of poorly water-soluble drugs and improvement of their solubility and bioavailability. Beyond conventional CD systems, stimulus-responsive CDNSs provide additional control by responding to internal or external triggers such as pH, temperature, light, and redox conditions. Particularly, glutathione-responsive CDNSs exploit intracellular redox gradients via disulfide bond cleavage, enabling selective drug release in cancerous and inflammatory tissues. Literature for this narrative review was identified through searches of PubMed, Web of Science, and Scopus, focusing on publications from 2000 to early 2025.

This review highlights glutathione-responsive cyclodextrin nanosponges as an advanced evolution of CD-based carriers, emphasizing emerging structure - property - responsiveness relationships rather than exhaustive coverage. By discussing nanosponge architecture and cross-linking density.