Cyclodextrin platforms for siRNA delivery: turning design into new therapies

Small interfering RNA (siRNA) is a powerful tool for post-transcriptional gene silencing, with profound therapeutic implications across a spectrum of diseases, including cancer, hereditary disorders, metabolic disorders, neurodegenerative disorders, and microbial infections. Despite extensive research on siRNA, its delivery remains a significant challenge due to its inherent instability, susceptibility to nuclease degradation, poor cellular uptake, and rapid renal clearance. Cyclodextrins (CDs), a family of cyclic oligosaccharides, have attracted significant attention as non-viral siRNA nanocarriers due to their unique physicochemical properties, such as a hydrophilic exterior, a hydrophobic cavity, biocompatibility, and the ability to form inclusion complexes with biomolecules. In this review, we explore the mechanism of CD-mediated siRNA delivery, emphasizing the design and functionalization of CD-based nanocarriers. Furthermore, CD-polyrotaxanes (PRs) and polymer-conjugated CDs provide enhanced stability and controlled siRNA release, while targeting ligand modifications improve systemic circulation and specificity. Herein, co-delivery of siRNA with therapeutics using CD-based carriers showed synergistic effects that enhance gene silencing and therapeutic efficacy. Moreover, innovative strategies, such as pH-responsive, enzyme-activated, and redox-sensitive CD-based systems, are being developed to improve siRNA bioavailability and intracellular trafficking. Finally, we consider the translational potential of these platforms, identifying key challenges and future perspectives that will shape the next generation of CD-based siRNA therapies.