A rationally designed polypeptide-based hybrid platform for targeted intranasal brain drug delivery
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...
| Autores: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2026 |
| País: | España |
| Institución: | Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO) |
| Repositorio: | r-FISABIO. Repositorio Institucional de Producción Científica |
| OAI Identifier: | oai:dnet:r-fisabio___::ee0e9c95511f1a0c42456eb864e48147 |
| Acceso en línea: | https://fisabio.portalinvestigacion.com/publicaciones/20797 https://www.scopus.com/inward/record.uri?eid=2-s2.0-105026616628&doi=10.1016%2fj.biomaterials.2025.123867&partnerID=40&md5=f3e4e06eb134a3f8ba1c655322293c59 |
| Access Level: | acceso abierto |
| Palabra clave: | Brain targeting HA-CP Hyaluronic acid-poly-L-glutamate cross-polymer Intranasal drug delivery Mucoadhesive nanocarriers Nose-to-brain transport Polypeptide Administration, Intranasal Animals Blood-Brain Barrier Brain Drug Delivery Systems Humans Hyaluronic Acid Hydrogels Mice Nasal Mucosa Peptides Biocompatibility Controlled drug delivery Crosslinking Diffusion Glycoproteins Hyaluronic acid Neurons Permeation Physicochemical properties biomaterial liposome nanocarrier nanoparticle polymer polypeptide hyaluronic acid hydrogel peptide Brain transport Intranasal L-glutamate Mucoadhesive nanocarrier Mucoadhesives Nanocarriers animal experiment animal model animal tissue Article blood brain barrier central nervous system controlled study drug absorption drug delivery system drug release ex vivo study histology |
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A rationally designed polypeptide-based hybrid platform for targeted intranasal brain drug deliveryConejos-Sánchez, I.Melnyk, T.Masiá, E.Morelló-Bolumar, D.Tortajada-Comeche, L.Dolz-Pérez, I.Torrijos-Saiz, L.I.Tenhaeff, P.Roosz, J.Moruzzi, A.Sogorb, G.Medel, M.Loskill, P.Roselló, E.Sebastian, V.Florindo, H.Felip-León, C.Nebot, V.J.Herranz-Pérez, V.García-Vedugo, J.M.Vicent, M.J.Brain targetingHA-CPHyaluronic acid-poly-L-glutamate cross-polymerIntranasal drug deliveryMucoadhesive nanocarriersNose-to-brain transportPolypeptideAdministration, IntranasalAnimalsBlood-Brain BarrierBrainDrug Delivery SystemsHumansHyaluronic AcidHydrogelsMiceNasal MucosaPeptidesBiocompatibilityBrainControlled drug deliveryCrosslinkingDiffusionGlycoproteinsHyaluronic acidNeuronsPermeationPhysicochemical propertiesbiomaterialliposomenanocarriernanoparticlepolymerpolypeptidehyaluronic acidhydrogelpeptideBrain targetingBrain transportHA-CPHyaluronic acid-poly-L-glutamate cross-polymerIntranasalIntranasal drug deliveryL-glutamateMucoadhesive nanocarrierMucoadhesivesNanocarriersNose-to-brain transportanimal experimentanimal modelanimal tissueArticleblood brain barriercentral nervous systemcontrolled studydrug absorptiondrug delivery systemdrug releaseex vivo studyhistologyIntranasal 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. © 2025 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license. http://creativecommons.org/licenses/by-nc-nd/4.0/ELSEVIER SCI LTD2026info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fisabio.portalinvestigacion.com/publicaciones/20797https://www.scopus.com/inward/record.uri?eid=2-s2.0-105026616628&doi=10.1016%2fj.biomaterials.2025.123867&partnerID=40&md5=f3e4e06eb134a3f8ba1c655322293c59BIOMATERIALSISSN: 01429612ISSNe: 18785905reponame:r-FISABIO. Repositorio Institucional de Producción Científicainstname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)Inglésinfo:eu-repo/semantics/openAccessoai:dnet:r-fisabio___::ee0e9c95511f1a0c42456eb864e481472026-06-11T12:45:17Z |
| dc.title.none.fl_str_mv |
A rationally designed polypeptide-based hybrid platform for targeted intranasal brain drug delivery |
| title |
A rationally designed polypeptide-based hybrid platform for targeted intranasal brain drug delivery |
| spellingShingle |
A rationally designed polypeptide-based hybrid platform for targeted intranasal brain drug delivery Conejos-Sánchez, I. Brain targeting HA-CP Hyaluronic acid-poly-L-glutamate cross-polymer Intranasal drug delivery Mucoadhesive nanocarriers Nose-to-brain transport Polypeptide Administration, Intranasal Animals Blood-Brain Barrier Brain Drug Delivery Systems Humans Hyaluronic Acid Hydrogels Mice Nasal Mucosa Peptides Biocompatibility Brain Controlled drug delivery Crosslinking Diffusion Glycoproteins Hyaluronic acid Neurons Permeation Physicochemical properties biomaterial liposome nanocarrier nanoparticle polymer polypeptide hyaluronic acid hydrogel peptide Brain targeting Brain transport HA-CP Hyaluronic acid-poly-L-glutamate cross-polymer Intranasal Intranasal drug delivery L-glutamate Mucoadhesive nanocarrier Mucoadhesives Nanocarriers Nose-to-brain transport animal experiment animal model animal tissue Article blood brain barrier central nervous system controlled study drug absorption drug delivery system drug release ex vivo study histology |
| title_short |
A rationally designed polypeptide-based hybrid platform for targeted intranasal brain drug delivery |
| title_full |
A rationally designed polypeptide-based hybrid platform for targeted intranasal brain drug delivery |
| title_fullStr |
A rationally designed polypeptide-based hybrid platform for targeted intranasal brain drug delivery |
| title_full_unstemmed |
A rationally designed polypeptide-based hybrid platform for targeted intranasal brain drug delivery |
| title_sort |
A rationally designed polypeptide-based hybrid platform for targeted intranasal brain drug delivery |
| dc.creator.none.fl_str_mv |
Conejos-Sánchez, I. Melnyk, T. Masiá, E. Morelló-Bolumar, D. Tortajada-Comeche, L. Dolz-Pérez, I. Torrijos-Saiz, L.I. Tenhaeff, P. Roosz, J. Moruzzi, A. Sogorb, G. Medel, M. Loskill, P. Roselló, E. Sebastian, V. Florindo, H. Felip-León, C. Nebot, V.J. Herranz-Pérez, V. García-Vedugo, J.M. Vicent, M.J. |
| author |
Conejos-Sánchez, I. |
| author_facet |
Conejos-Sánchez, I. Melnyk, T. Masiá, E. Morelló-Bolumar, D. Tortajada-Comeche, L. Dolz-Pérez, I. Torrijos-Saiz, L.I. Tenhaeff, P. Roosz, J. Moruzzi, A. Sogorb, G. Medel, M. Loskill, P. Roselló, E. Sebastian, V. Florindo, H. Felip-León, C. Nebot, V.J. Herranz-Pérez, V. García-Vedugo, J.M. Vicent, M.J. |
| author_role |
author |
| author2 |
Melnyk, T. Masiá, E. Morelló-Bolumar, D. Tortajada-Comeche, L. Dolz-Pérez, I. Torrijos-Saiz, L.I. Tenhaeff, P. Roosz, J. Moruzzi, A. Sogorb, G. Medel, M. Loskill, P. Roselló, E. Sebastian, V. Florindo, H. Felip-León, C. Nebot, V.J. Herranz-Pérez, V. García-Vedugo, J.M. Vicent, M.J. |
| author2_role |
author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Brain targeting HA-CP Hyaluronic acid-poly-L-glutamate cross-polymer Intranasal drug delivery Mucoadhesive nanocarriers Nose-to-brain transport Polypeptide Administration, Intranasal Animals Blood-Brain Barrier Brain Drug Delivery Systems Humans Hyaluronic Acid Hydrogels Mice Nasal Mucosa Peptides Biocompatibility Brain Controlled drug delivery Crosslinking Diffusion Glycoproteins Hyaluronic acid Neurons Permeation Physicochemical properties biomaterial liposome nanocarrier nanoparticle polymer polypeptide hyaluronic acid hydrogel peptide Brain targeting Brain transport HA-CP Hyaluronic acid-poly-L-glutamate cross-polymer Intranasal Intranasal drug delivery L-glutamate Mucoadhesive nanocarrier Mucoadhesives Nanocarriers Nose-to-brain transport animal experiment animal model animal tissue Article blood brain barrier central nervous system controlled study drug absorption drug delivery system drug release ex vivo study histology |
| topic |
Brain targeting HA-CP Hyaluronic acid-poly-L-glutamate cross-polymer Intranasal drug delivery Mucoadhesive nanocarriers Nose-to-brain transport Polypeptide Administration, Intranasal Animals Blood-Brain Barrier Brain Drug Delivery Systems Humans Hyaluronic Acid Hydrogels Mice Nasal Mucosa Peptides Biocompatibility Brain Controlled drug delivery Crosslinking Diffusion Glycoproteins Hyaluronic acid Neurons Permeation Physicochemical properties biomaterial liposome nanocarrier nanoparticle polymer polypeptide hyaluronic acid hydrogel peptide Brain targeting Brain transport HA-CP Hyaluronic acid-poly-L-glutamate cross-polymer Intranasal Intranasal drug delivery L-glutamate Mucoadhesive nanocarrier Mucoadhesives Nanocarriers Nose-to-brain transport animal experiment animal model animal tissue Article blood brain barrier central nervous system controlled study drug absorption drug delivery system drug release ex vivo study histology |
| description |
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. © 2025 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license. http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| publishDate |
2026 |
| dc.date.none.fl_str_mv |
2026 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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https://fisabio.portalinvestigacion.com/publicaciones/20797 https://www.scopus.com/inward/record.uri?eid=2-s2.0-105026616628&doi=10.1016%2fj.biomaterials.2025.123867&partnerID=40&md5=f3e4e06eb134a3f8ba1c655322293c59 |
| url |
https://fisabio.portalinvestigacion.com/publicaciones/20797 https://www.scopus.com/inward/record.uri?eid=2-s2.0-105026616628&doi=10.1016%2fj.biomaterials.2025.123867&partnerID=40&md5=f3e4e06eb134a3f8ba1c655322293c59 |
| dc.language.none.fl_str_mv |
Inglés |
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Inglés |
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info:eu-repo/semantics/openAccess |
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openAccess |
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ELSEVIER SCI LTD |
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ELSEVIER SCI LTD |
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BIOMATERIALS ISSN: 01429612 ISSNe: 18785905 reponame:r-FISABIO. Repositorio Institucional de Producción Científica instname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO) |
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Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO) |
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r-FISABIO. Repositorio Institucional de Producción Científica |
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r-FISABIO. Repositorio Institucional de Producción Científica |
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1869420199858405376 |
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15.811543 |