Encapsulation of Dexamethasone into mRNA–Lipid Nanoparticles Is a Promising Approach for the Development of Liver-Targeted Anti-Inflammatory Therapies

Autores
Rivero Berti, Ignacio; Gambaro, Rocío Celeste; Limeres, María José; Huck Iriart, Cristián; Svensson, Malin; Fraude El Ghazi, Silvia; Pretsch, Leah; Si, Shutian; Lieberwirth, Ingo; Landfester, Katharina; Cacicedo, Maximiliano Luis; Islan, German Abel; Gehring, Stephan
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The objective of this study was to develop two lipid nanoparticle (LNP) formulations capable of efficiently expressing a reporter mRNA while co-delivering the anti-inflammatory drug dexamethasone (DX) to reduce inflammatory side effects in protein replacement therapies. Two types of LNPs were developed, in which 25% of cholesterol was replaced by DX. These LNPs contained either 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) as a helper lipid. The resulting LNPs exhibited high stability, homogeneity, and near-neutral Zeta potentials. SAXS experiments confirmed DX incorporation into the LNP core, with slow in vitro DX release observed over 48 h. The LNPs achieved high mRNA encapsulation efficiency (95–100%) and effectively transfected HepG2 cells, dendritic cells, and hPBMCs. While LNPs increased cytokine release (IL-1β, TNF-α, MCP-1), LNPs-DX significantly reduced cytokine levels, demonstrating enhanced anti-inflammatory properties while maintaining mRNA expression levels. In vivo biodistribution showed predominant liver localization post-intramuscular injection, regardless of the DSPC or DOPE composition. LNPs co-loaded with mRNA and DX are promising candidates for continuous protein replacement. Due to their ability to reduce treatment-related inflammation while maintaining significant mRNA expression levels, these LNPs are perfectly suited for the treatment of liver-related metabolic diseases.
Fil: Rivero Berti, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; Argentina. Johannes Gutenberg Universitat Mainz; Alemania
Fil: Gambaro, Rocío Celeste. Johannes Gutenberg Universitat Mainz; Alemania
Fil: Limeres, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina. Johannes Gutenberg Universitat Mainz; Alemania
Fil: Huck Iriart, Cristián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; Argentina. Alba - Synchrotron Light Source.; España
Fil: Svensson, Malin. Johannes Gutenberg Universitat Mainz; Alemania
Fil: Fraude El Ghazi, Silvia. Johannes Gutenberg Universitat Mainz; Alemania
Fil: Pretsch, Leah. Johannes Gutenberg Universitat Mainz; Alemania
Fil: Si, Shutian. Max-Planck-Institut für Polymerforschung; Alemania
Fil: Lieberwirth, Ingo. Max-Planck-Institut für Polymerforschung; Alemania
Fil: Landfester, Katharina. Max-Planck-Institut für Polymerforschung; Alemania
Fil: Cacicedo, Maximiliano Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; Argentina. Johannes Gutenberg Universitat Mainz; Alemania
Fil: Islan, German Abel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; Argentina. Johannes Gutenberg Universitat Mainz; Alemania
Fil: Gehring, Stephan. Johannes Gutenberg Universitat Mainz; Alemania
Materia
Lipid nanoparticles
mRNA DELIVERY
Dexamethasone
Cytokines
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/266075
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/266075
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Encapsulation of Dexamethasone into mRNA–Lipid Nanoparticles Is a Promising Approach for the Development of Liver-Targeted Anti-Inflammatory TherapiesRivero Berti, IgnacioGambaro, Rocío CelesteLimeres, María JoséHuck Iriart, CristiánSvensson, MalinFraude El Ghazi, SilviaPretsch, LeahSi, ShutianLieberwirth, IngoLandfester, KatharinaCacicedo, Maximiliano LuisIslan, German AbelGehring, StephanLipid nanoparticlesmRNA DELIVERYDexamethasoneCytokineshttps://purl.org/becyt/ford/3.4https://purl.org/becyt/ford/3The objective of this study was to develop two lipid nanoparticle (LNP) formulations capable of efficiently expressing a reporter mRNA while co-delivering the anti-inflammatory drug dexamethasone (DX) to reduce inflammatory side effects in protein replacement therapies. Two types of LNPs were developed, in which 25% of cholesterol was replaced by DX. These LNPs contained either 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) as a helper lipid. The resulting LNPs exhibited high stability, homogeneity, and near-neutral Zeta potentials. SAXS experiments confirmed DX incorporation into the LNP core, with slow in vitro DX release observed over 48 h. The LNPs achieved high mRNA encapsulation efficiency (95–100%) and effectively transfected HepG2 cells, dendritic cells, and hPBMCs. While LNPs increased cytokine release (IL-1β, TNF-α, MCP-1), LNPs-DX significantly reduced cytokine levels, demonstrating enhanced anti-inflammatory properties while maintaining mRNA expression levels. In vivo biodistribution showed predominant liver localization post-intramuscular injection, regardless of the DSPC or DOPE composition. LNPs co-loaded with mRNA and DX are promising candidates for continuous protein replacement. Due to their ability to reduce treatment-related inflammation while maintaining significant mRNA expression levels, these LNPs are perfectly suited for the treatment of liver-related metabolic diseases.Fil: Rivero Berti, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; Argentina. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Gambaro, Rocío Celeste. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Limeres, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Huck Iriart, Cristián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; Argentina. Alba - Synchrotron Light Source.; EspañaFil: Svensson, Malin. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Fraude El Ghazi, Silvia. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Pretsch, Leah. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Si, Shutian. Max-Planck-Institut für Polymerforschung; AlemaniaFil: Lieberwirth, Ingo. Max-Planck-Institut für Polymerforschung; AlemaniaFil: Landfester, Katharina. Max-Planck-Institut für Polymerforschung; AlemaniaFil: Cacicedo, Maximiliano Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; Argentina. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Islan, German Abel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; Argentina. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Gehring, Stephan. Johannes Gutenberg Universitat Mainz; AlemaniaMolecular Diversity Preservation International2024-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/266075Rivero Berti, Ignacio; Gambaro, Rocío Celeste; Limeres, María José; Huck Iriart, Cristián; Svensson, Malin; et al.; Encapsulation of Dexamethasone into mRNA–Lipid Nanoparticles Is a Promising Approach for the Development of Liver-Targeted Anti-Inflammatory Therapies; Molecular Diversity Preservation International; International Journal of Molecular Sciences; 25; 20; 10-2024; 1-231422-0067CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1422-0067/25/20/11254info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms252011254info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:46:07Zoai:ri.conicet.gov.ar:11336/266075instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:46:07.381CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Encapsulation of Dexamethasone into mRNA–Lipid Nanoparticles Is a Promising Approach for the Development of Liver-Targeted Anti-Inflammatory Therapies
title Encapsulation of Dexamethasone into mRNA–Lipid Nanoparticles Is a Promising Approach for the Development of Liver-Targeted Anti-Inflammatory Therapies
spellingShingle Encapsulation of Dexamethasone into mRNA–Lipid Nanoparticles Is a Promising Approach for the Development of Liver-Targeted Anti-Inflammatory Therapies
Rivero Berti, Ignacio
Lipid nanoparticles
mRNA DELIVERY
Dexamethasone
Cytokines
title_short Encapsulation of Dexamethasone into mRNA–Lipid Nanoparticles Is a Promising Approach for the Development of Liver-Targeted Anti-Inflammatory Therapies
title_full Encapsulation of Dexamethasone into mRNA–Lipid Nanoparticles Is a Promising Approach for the Development of Liver-Targeted Anti-Inflammatory Therapies
title_fullStr Encapsulation of Dexamethasone into mRNA–Lipid Nanoparticles Is a Promising Approach for the Development of Liver-Targeted Anti-Inflammatory Therapies
title_full_unstemmed Encapsulation of Dexamethasone into mRNA–Lipid Nanoparticles Is a Promising Approach for the Development of Liver-Targeted Anti-Inflammatory Therapies
title_sort Encapsulation of Dexamethasone into mRNA–Lipid Nanoparticles Is a Promising Approach for the Development of Liver-Targeted Anti-Inflammatory Therapies
dc.creator.none.fl_str_mv Rivero Berti, Ignacio
Gambaro, Rocío Celeste
Limeres, María José
Huck Iriart, Cristián
Svensson, Malin
Fraude El Ghazi, Silvia
Pretsch, Leah
Si, Shutian
Lieberwirth, Ingo
Landfester, Katharina
Cacicedo, Maximiliano Luis
Islan, German Abel
Gehring, Stephan
author Rivero Berti, Ignacio
author_facet Rivero Berti, Ignacio
Gambaro, Rocío Celeste
Limeres, María José
Huck Iriart, Cristián
Svensson, Malin
Fraude El Ghazi, Silvia
Pretsch, Leah
Si, Shutian
Lieberwirth, Ingo
Landfester, Katharina
Cacicedo, Maximiliano Luis
Islan, German Abel
Gehring, Stephan
author_role author
author2 Gambaro, Rocío Celeste
Limeres, María José
Huck Iriart, Cristián
Svensson, Malin
Fraude El Ghazi, Silvia
Pretsch, Leah
Si, Shutian
Lieberwirth, Ingo
Landfester, Katharina
Cacicedo, Maximiliano Luis
Islan, German Abel
Gehring, Stephan
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Lipid nanoparticles
mRNA DELIVERY
Dexamethasone
Cytokines
topic Lipid nanoparticles
mRNA DELIVERY
Dexamethasone
Cytokines
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.4
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The objective of this study was to develop two lipid nanoparticle (LNP) formulations capable of efficiently expressing a reporter mRNA while co-delivering the anti-inflammatory drug dexamethasone (DX) to reduce inflammatory side effects in protein replacement therapies. Two types of LNPs were developed, in which 25% of cholesterol was replaced by DX. These LNPs contained either 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) as a helper lipid. The resulting LNPs exhibited high stability, homogeneity, and near-neutral Zeta potentials. SAXS experiments confirmed DX incorporation into the LNP core, with slow in vitro DX release observed over 48 h. The LNPs achieved high mRNA encapsulation efficiency (95–100%) and effectively transfected HepG2 cells, dendritic cells, and hPBMCs. While LNPs increased cytokine release (IL-1β, TNF-α, MCP-1), LNPs-DX significantly reduced cytokine levels, demonstrating enhanced anti-inflammatory properties while maintaining mRNA expression levels. In vivo biodistribution showed predominant liver localization post-intramuscular injection, regardless of the DSPC or DOPE composition. LNPs co-loaded with mRNA and DX are promising candidates for continuous protein replacement. Due to their ability to reduce treatment-related inflammation while maintaining significant mRNA expression levels, these LNPs are perfectly suited for the treatment of liver-related metabolic diseases.
Fil: Rivero Berti, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; Argentina. Johannes Gutenberg Universitat Mainz; Alemania
Fil: Gambaro, Rocío Celeste. Johannes Gutenberg Universitat Mainz; Alemania
Fil: Limeres, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina. Johannes Gutenberg Universitat Mainz; Alemania
Fil: Huck Iriart, Cristián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; Argentina. Alba - Synchrotron Light Source.; España
Fil: Svensson, Malin. Johannes Gutenberg Universitat Mainz; Alemania
Fil: Fraude El Ghazi, Silvia. Johannes Gutenberg Universitat Mainz; Alemania
Fil: Pretsch, Leah. Johannes Gutenberg Universitat Mainz; Alemania
Fil: Si, Shutian. Max-Planck-Institut für Polymerforschung; Alemania
Fil: Lieberwirth, Ingo. Max-Planck-Institut für Polymerforschung; Alemania
Fil: Landfester, Katharina. Max-Planck-Institut für Polymerforschung; Alemania
Fil: Cacicedo, Maximiliano Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; Argentina. Johannes Gutenberg Universitat Mainz; Alemania
Fil: Islan, German Abel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; Argentina. Johannes Gutenberg Universitat Mainz; Alemania
Fil: Gehring, Stephan. Johannes Gutenberg Universitat Mainz; Alemania
description The objective of this study was to develop two lipid nanoparticle (LNP) formulations capable of efficiently expressing a reporter mRNA while co-delivering the anti-inflammatory drug dexamethasone (DX) to reduce inflammatory side effects in protein replacement therapies. Two types of LNPs were developed, in which 25% of cholesterol was replaced by DX. These LNPs contained either 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) as a helper lipid. The resulting LNPs exhibited high stability, homogeneity, and near-neutral Zeta potentials. SAXS experiments confirmed DX incorporation into the LNP core, with slow in vitro DX release observed over 48 h. The LNPs achieved high mRNA encapsulation efficiency (95–100%) and effectively transfected HepG2 cells, dendritic cells, and hPBMCs. While LNPs increased cytokine release (IL-1β, TNF-α, MCP-1), LNPs-DX significantly reduced cytokine levels, demonstrating enhanced anti-inflammatory properties while maintaining mRNA expression levels. In vivo biodistribution showed predominant liver localization post-intramuscular injection, regardless of the DSPC or DOPE composition. LNPs co-loaded with mRNA and DX are promising candidates for continuous protein replacement. Due to their ability to reduce treatment-related inflammation while maintaining significant mRNA expression levels, these LNPs are perfectly suited for the treatment of liver-related metabolic diseases.
publishDate 2024
dc.date.none.fl_str_mv 2024-10
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/266075
Rivero Berti, Ignacio; Gambaro, Rocío Celeste; Limeres, María José; Huck Iriart, Cristián; Svensson, Malin; et al.; Encapsulation of Dexamethasone into mRNA–Lipid Nanoparticles Is a Promising Approach for the Development of Liver-Targeted Anti-Inflammatory Therapies; Molecular Diversity Preservation International; International Journal of Molecular Sciences; 25; 20; 10-2024; 1-23
1422-0067
CONICET Digital
CONICET
url http://hdl.handle.net/11336/266075
identifier_str_mv Rivero Berti, Ignacio; Gambaro, Rocío Celeste; Limeres, María José; Huck Iriart, Cristián; Svensson, Malin; et al.; Encapsulation of Dexamethasone into mRNA–Lipid Nanoparticles Is a Promising Approach for the Development of Liver-Targeted Anti-Inflammatory Therapies; Molecular Diversity Preservation International; International Journal of Molecular Sciences; 25; 20; 10-2024; 1-23
1422-0067
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1422-0067/25/20/11254
info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms252011254
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Molecular Diversity Preservation International
publisher.none.fl_str_mv Molecular Diversity Preservation International
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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