Harnessing Supramolecular Chemistry for Gene Therapy: Cyclodextrin-Based Platforms for Nucleic Acid Delivery

At the interface between chemistry and medicine, supramolecular assemblies are emerging as versatile platforms for therapeutic delivery. Their reversible non-covalent interactions and chemically tunable architectures allow the design of adaptive systems capable of transporting not only conventional small molecules, but also fragile biological macromolecules.¹

In this context, gene therapy is emerging as a transformative approach for cancer, metabolic disorders, and rare diseases, enabling modulation or correction of defective genes and gene products.² However, the clinical translation of therapeutic nucleic acids, including miRNAs, anti-miRNAs, and related oligonucleotides, remains limited by poor membrane permeability, high hydrophilicity, large size, and rapid enzymatic degradation, requiring safe, biocompatible, and non-viral delivery systems.³

β-Cyclodextrin (β-CD) represents a privileged supramolecular building block for this purpose. Its hydrophobic cavity, hydrophilic surface, and derivatizable hydroxyl groups enable complex architectures, including first-generation β-CD-based nanosponges (NS). These crosslinked polymeric systems combine host-guest inclusion, porous macromolecular organization, and opportunities for functional modification. In our design, bridge-like molecules (BLMs) based on cationic adamantyl derivatives can act as supramolecular connectors, promoting simultaneous interaction with the β-CD cavity and the anionic phosphate backbone of therapeutic nucleic acids.⁴

These modular platforms provide a proof of concept for supramolecular assemblies supporting nucleic acid delivery. Conceived for topical ocular administration, they may guide further optimization toward local or systemic applications in next-generation gene therapy.

This work was funded by the European Union – NextGenerationEU, Mission 4 Component 2, CUP I53C22000710007.