Abstract
Small interfering RNA (siRNA) holds significant therapeutic potential for a broad range of diseases, including diseases of the central nervous system, yet its clinical translation remains limited by the lack of efficient and targeted delivery strategies, largely due to poor membrane permeability. To address this challenge, we developed a multifunctional RNA delivery platform by integrating positively charged cell-penetrating peptide sequences into the lectin-mimicking cyclic peptide odorranalectin (OL), which has demonstrated nose-to-brain transport capability. Placement of the cationic sequence at the N-terminus minimizes steric interference between functional domains, preserving the intrinsic carbohydrate-binding capability of the OL scaffold while enabling efficient RNA association. Peptides containing higher numbers of cationic residues exhibited enhanced RNA binding, as assessed by electrophoretic mobility shift assays and by increased thermal stability of peptide/RNA complexes measured using circular dichroism spectroscopy. Importantly, incorporation of the cationic sequence did not compromise carbohydrate recognition, as confirmed by isothermal titration calorimetry using OL-TAT and asialofetuin as a model system. Collectively, these results support the development of OL-based bifunctional ligands with tunable RNA and carbohydrate recognition and underscore their potential as intranasal platforms for targeted siRNA delivery to the brain.