A rationally designed polypeptide-based hybrid platform for targeted intranasal brain drug delivery

Conejos-Sánchez, Inmaculada ; 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) ; Florindo, Helena ; Felip-León, Carles ; Nebot, Vicent J. ; Herranz-Pérez, Vicente ; García-Vedugo, José Manuel ; Vicent, María J.

Resumen: 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.

Idioma: Inglés

DOI: 10.1016/j.biomaterials.2025.123867

Año: 2025

Publicado en: Biomaterials 328 (2025), 123867 [19 pp.]
ISSN: 0142-9612

Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2021-127847OB-I00
Financiación: info:eu-repo/grantAgreement/ES/MICIU/CEX2023-001286-S

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Ingeniería Química (Dpto. Ing.Quím.Tecnol.Med.Amb.)