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

I. Conejos-Sánchez et al.

Detalles Bibliográficos
Autores: Conejos-Sánchez, Inmaculada, Sebastián, Víctor, Vicent, María J.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2026
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/425286
Acceso en línea:http://hdl.handle.net/10261/425286
Access Level:acceso abierto
Palabra clave:Brain targeting
Polypeptide
HA-CP
Nose-to-brain transport
Hyaluronic acid-poly-L-glutamate cross-polymer
Mucoadhesive nanocarriers
Intranasal drug delivery
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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, Inmaculada
Brain targeting
Polypeptide
HA-CP
Nose-to-brain transport
Hyaluronic acid-poly-L-glutamate cross-polymer
Mucoadhesive nanocarriers
Intranasal drug delivery
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, Inmaculada
Sebastián, Víctor
Vicent, María J.
author Conejos-Sánchez, Inmaculada
author_facet Conejos-Sánchez, Inmaculada
Sebastián, Víctor
Vicent, María J.
author_role author
author2 Sebastián, Víctor
Vicent, María J.
author2_role author
author
dc.contributor.none.fl_str_mv European Commission
European Research Council
Fundación la Caixa
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Ministerio de Economía y Competitividad (España)
Generalitat Valenciana
Asociación Española Contra el Cáncer
Agència Valenciana de la Innovació
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Brain targeting
Polypeptide
HA-CP
Nose-to-brain transport
Hyaluronic acid-poly-L-glutamate cross-polymer
Mucoadhesive nanocarriers
Intranasal drug delivery
topic Brain targeting
Polypeptide
HA-CP
Nose-to-brain transport
Hyaluronic acid-poly-L-glutamate cross-polymer
Mucoadhesive nanocarriers
Intranasal drug delivery
description I. Conejos-Sánchez et al.
publishDate 2026
dc.date.none.fl_str_mv 2026
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
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dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/425286
url http://hdl.handle.net/10261/425286
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI 10.1016/j.biomaterials.2025.123867
https://doi.org/10.1016/j.biomaterials.2025.123867
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dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
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spelling A rationally designed polypeptide-based hybrid platform for targeted intranasal brain drug deliveryConejos-Sánchez, InmaculadaSebastián, VíctorVicent, María J.Brain targetingPolypeptideHA-CPNose-to-brain transportHyaluronic acid-poly-L-glutamate cross-polymerMucoadhesive nanocarriersIntranasal drug deliveryI. Conejos-Sánchez et al.Data will be made available on request.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.This work was supported by the European Research Council (grant ERC-CoG-2014-648831 ″MyNano” and ERC-PoC- 2022-POC1 ″POLYBRAINT”) to M.J.V.); Health Foundation La Caixa Research Project NanoGBA (HR22-00602) and Caixa Impulse NanoERT (CI24-20222); the Spanish Ministry of Science, Innovation, and Universities (SAF2016-80427-R, PID2019-108806RB-I00 to M.J.V.; RTC-2017-6465-1, C.F-L Grant PTQ2018-010251 and D.M − B, Grant Industrial PhD DI-14-06926); the MINECO/FEDER, UE; European Regional Development Fund (ERDF) included in the ERDF operational program of Comunidad Valenciana 2014-2020; the Valencian Council for Education, Culture, University and Employment (CIPROM/2023/053) to J.M.G-V and V.H-P; the Valencian Innovation Agency (AVI) (L.T-C INNTAL31/19/005) and the Generalitat Valenciana (I.D-P, Grant VALi+d ACIF-2016-021 and BEFPI/2018/055). I.C-S. is funded by AEEC Junior Grant (Ref INVES211323CONE), and L.I.T.-S. has a predoctoral contract by the Valencian Council for Education, Universities and Employment (ACIF2021/420). VS acknowledges funding from project PID2024-160339OB-I00, PID2021-127847OB-I00, ‘Severo Ochoa’ Programme for Centres of Excellence in R&D of the Spanish Ministry of Science, Innovation and Universities (MICIU CEX2023-001286-S MICIU/AEI /10.13039/501100011033).With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX2023-001286-S).Peer reviewedElsevierEuropean CommissionEuropean Research CouncilFundación la CaixaMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Ministerio de Economía y Competitividad (España)Generalitat ValencianaAsociación Española Contra el CáncerAgència Valenciana de la InnovacióConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262026info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/425286reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/EC/H2020/648831info:eu-repo/grantAgreement/AEI//SAF2016-80427-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-108806RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTC-2017-6465-1info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PTQ2018-010251info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2024-2027/PID2024-160339OB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-127847OB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/CEX2023-001286-SThe underlying dataset has been published as supplementary material of the article in the publisher platform at DOI 10.1016/j.biomaterials.2025.123867https://doi.org/10.1016/j.biomaterials.2025.123867Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4252862026-05-22T06:33:51Z
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