168458 20260205155159.0 doi 10.1016/j.biomaterials.2025.123867 sideral 147912 ART-2025-147912 eng Conejos-Sánchez, Inmaculada A rationally designed polypeptide-based hybrid platform for targeted intranasal brain drug delivery 2025 Intranasal administration represents a safe and non-invasive route for drug delivery to the brain; however, clinical translation remains limited due to anatomical and physiological barriers. We present a modular hybrid biomaterial platform (NanoInBrain) that bypasses the blood-brain barrier via the olfactory route and enables central nervous system (CNS) drug delivery. The platform integrates a rationally designed polypeptide-based nanocarrier with a depot-forming hydrogel vehicle - a hyaluronic acid–poly-L-glutamate crosspolymer (HA-CP, Yalic®) - adapted from dermatological applications to enhance nasal mucosal retention and brain uptake. We engineered the nanocarrier system using star-shaped poly-L-glutamate (StPGA) architectures and systematically tuned physicochemical properties to optimize mucosal interaction and CNS diffusion. We introduced mucoadhesive and mucodiffusive functionalities via C-terminal odorranalectin (OL) conjugation, which improved nasal epithelium permeation through receptor-mediated mechanisms. Redox-responsive disulfide crosslinking (StPGA-CL-SS) further enhanced mucosal transport by enabling thiol-mediated anchoring to mucin glycoproteins, outperforming inert click-crosslinked variants. Ex vivo Franz diffusion studies and a nasal-mucosa-on-chip model demonstrated robust permeation, with in vivo imaging confirming brain distribution and intracellular uptake in neurons and microglia. Incorporation of HA-CP prolonged nasal residence (∼4 h) and increased total brain accumulation while being well-tolerated. This new platform combines architectural tunability, bioresponsive surface chemistry, and depot-mediated delivery in a scalable, biocompatible nose-to-brain delivery system with potential for treating neurological disorders. Access copy available to the general public Unrestricted info:eu-repo/grantAgreement/ES/MICINN/PID2021-127847OB-I00 info:eu-repo/grantAgreement/ES/MICIU/CEX2023-001286-S info:eu-repo/semantics/openAccess by-nc-nd https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Melnyk, Tetiana Masiá, Esther Morelló-Bolumar, Daniel Tortajada-Comeche, Luz Dolz-Pérez, Irene Torrijos-Saiz, Lucía Inés Tenhaeff, Paula Roosz, Julia Moruzzi, Alessia Sogorb, Gloria Medel, Maria Loskill, Peter Roselló, Esther Sebastian, Victor Universidad de Zaragoza (orcid)0000-0002-6873-5244 Florindo, Helena Felip-León, Carles Nebot, Vicent J. Herranz-Pérez, Vicente García-Vedugo, José Manuel Vicent, María J. 5005 555 Universidad de Zaragoza Dpto. Ing.Quím.Tecnol.Med.Amb. Área Ingeniería Química 328 (2025), 123867 [19 pp.] Biomaterials Biomaterials 0142-9612 9546786 http://zaguan.unizar.es/record/168458/files/texto_completo.pdf Versión publicada 2524963 http://zaguan.unizar.es/record/168458/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:168458 articulos driver 2026-02-05-14:36:59 ARTICLE