Tetrahedral Framework Nucleic Acids as an Efficient Nasal‐to‐Brain Delivery Carrier via Neural Transport Pathways

Abstract In the development of nasal‐to‐brain (N2B) drug delivery systems, the key challenge lies in penetrating the mucus, crossing the nasal epithelial barrier, and achieving broad distribution within the central nervous system (CNS) while ensuring biosafety. Non‐biomimetic delivery systems raise concerns regarding metabolism, while biomimetic systems, though safer, still face premature drug release into nasal tissues and limited distribution. Moreover, the N2B transport mechanisms of most existing drug delivery systems remain inadequately understood. This study proposed an efficient nasal‐to‐brain delivery system based on tetrahedral framework nucleic acids (tFNAs). These nanostructures, ≈10 nm in size, possess densely negative‐charged surfaces that help evade protein capture in mucus, facilitate rapid penetration of the mucus layer, and travel along the olfactory and trigeminal nerve axons to achieve widespread distribution in the CNS. The transport pathway is clearly elucidated. Additionally, tFNAs are used to deliver peptide via intranasal administration to treat sepsis‐associated encephalopathy (SAE). Results showed that tFNA‐NAP can regulate microglial activity, reduce neuronal damage, and improve behavioral outcomes. Moreover, both short‐ and long‐term safety experiments revealed no adverse effects. In summary, the development of the tFNA‐based N2B delivery system fills a gap in this field, offering a non‐invasive treatment approach for CNS diseases.