Composition-Programmed Transport Inversion in Spherical Nucleic Acids across Distinct Epithelial Barriers

Can surface composition alone, while nanostructural topology is held constant, reverse transport preference across distinct biological barriers? Here, we address this question using barrier-adaptive spherical nucleic acids, or BASNAs, a fully organic and reducible polymeric SNA framework in which FcεRIβ-targeting antisense oligonucleotides (ASO) and zwitterionic poly(carboxybetaine) (pCB) chains are covalently cografted onto a shared scaffold, while only their relative surface composition is varied. Systematic modulation of the pCB-to-ASO ratio programs the interfacial state of the BASNA corona and produces composition-dependent transport inversion between two biophysically distinct epithelial barriers. Higher pCB content generates a highly hydrated interface that suppresses adhesive interactions with mucins and enables efficient diffusion through mucus, whereas lower pCB content preserves colloidal stability under mildly acidic conditions and supports transport across the stratum corneum. Across this composition series, BASNAs retain sequence-specific hybridization activity, exhibit enhanced duplex stability and nuclease resistance, and improve intracellular delivery. In vivo, barrier-matched BASNA formulations achieve FcεRIβ silencing in mast cells, preventing inflammatory flare-ups in a prophylactic atopic dermatitis model and suppressing established symptoms in a therapeutic allergic rhinitis model. These findings show that interfacial composition can serve as a control parameter for reversing barrier preference within a fixed nucleic acid nanostructure.