Giovanni Petrarolo

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. In this context, gene therapy emerges as a transformative approach for cancer, metabolic disorders, and rare diseases, enabling modulation or correction of defective genes and gene products. 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. 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 (NSs). 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. 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.

Alzheimer’s disease (AD) involves oxidative stress, metal dyshomeostasis, and toxic oligomers of the amyloid-β peptide (Aβ_1-42), calling for multifunctional agents. We investigated a panel of imidazo[1,2-a]pyridines bearing catechol or resorcinol motifs previously designed as SIRT1-activating agents. Their antioxidant profile was evaluated using in vitro DPPH and ABTS assays, which revealed promising radical scavenging activities, and TBARS assays on rat brain homogenates showing inhibition of lipid peroxidation, strictly dependent on the phenolic pattern. UV–Vis studies revealed metal-binding properties, particularly Cu²⁺ and Fe²⁺ interactions. In Aβ_1-42 aggregation assays, the most active derivatives appeared to promote fibril maturation and the growth of large, ThT-low aggregates with distinct morphological features observed by TEM. Notably, Aβ_1-42 aggregates generated in the presence of these compounds exhibited reduced cytotoxicity, preserved cell viability, and induced lower ROS levels in RA-differentiated SH-SY5Y cells compared to aggregates formed in their absence. Imaging and FRET analyses further indicated reduced formation of membrane-binding toxic species. Overall, our data suggest that polyphenolic imidazo[1,2-a]pyridines can remodel Aβ_1-42 aggregation, redirecting it toward structurally distinct and less toxic assemblies, while also counteracting oxidative and metal-associated damage. These findings highlight their potential as multifunctional agents capable of addressing several pathological hallmarks of AD.