Multifunctional Polypeptide-Based Nanoconjugates for Targeted Mitochondrial Delivery and Nonviral Gene Therapy

Autores
Pegoraro, Camilla; Masiá Sanchis, Esther; Dordevic, Snezana; Dolz Pérez, Irene; Huck Iriart, Cristián; Herrera, Lidia; Esteban Pérez, Sergio; Conejos Sanchez, Inmaculada; Vicent, María J.
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Despite recent advances in nanomedicine, developing multifunctional nanocarriers capable of targeted subcellular delivery and efficient gene therapy remains a significant challenge. This study reports the design, synthesis, and evaluation of a novel multifunctional polypeptide-based nanoconjugate that addresses this gap using sequential delivery, combining mitochondrial targeting and nonviral gene therapy. We engineered a poly-l-ornithine-based, polyethylene glycol-modified carrier and introduced a novel custom-designed trivalent compound (TRV3) into the structure. TRV3, conjugated to the polypeptide carrier via a redox-sensitive disulfide linker, incorporates the well-described triphenylphosphonium moiety (TPP) for mitochondrial targeting and a Cy5 fluorophore as a model drug. The resulting nanoconjugate (C-TRV3-A) demonstrated efficient endosomal escape and mitochondrial localization. Leveraging the endosomolytic properties of C-TRV3-A, we explored its potential as a nonviral vector for gene therapy. After optimizing formulation stability using a VLC-3 anionic polypeptide coating, we developed plasmid DNA polyplexes that exhibited enhanced stability and transfection efficiency in basic and advanced triple-negative breast cancer cell culture models. This multifunctional polypeptide-based nanoconjugate represents a significant advance in the field, offering a chemically versatile platform for simultaneous subcellular targeting and gene delivery that may be used in targeted cancer treatments, among other pathologies.
Fil: Pegoraro, Camilla. Príncipe Felipe Research Center; España
Fil: Masiá Sanchis, Esther. Instituto de Salud Carlos III; España. Príncipe Felipe Research Center; España
Fil: Dordevic, Snezana. No especifíca;
Fil: Dolz Pérez, Irene. No especifíca;
Fil: Huck Iriart, Cristián. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Instituto de Tecnologias Emergentes y Ciencias Aplicadas. - Universidad Nacional de San Martin. Instituto de Tecnologias Emergentes y Ciencias Aplicadas.; Argentina
Fil: Herrera, Lidia. No especifíca;
Fil: Esteban Pérez, Sergio. No especifíca;
Fil: Conejos Sanchez, Inmaculada. Instituto de Salud Carlos III; España
Fil: Vicent, María J.. Instituto de Salud Carlos III; España
Materia
gene therapy
proline
polypeptide
drug delivery
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/276539
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/276539
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Multifunctional Polypeptide-Based Nanoconjugates for Targeted Mitochondrial Delivery and Nonviral Gene TherapyPegoraro, CamillaMasiá Sanchis, EstherDordevic, SnezanaDolz Pérez, IreneHuck Iriart, CristiánHerrera, LidiaEsteban Pérez, SergioConejos Sanchez, InmaculadaVicent, María J.gene therapyprolinepolypeptidedrug deliveryhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Despite recent advances in nanomedicine, developing multifunctional nanocarriers capable of targeted subcellular delivery and efficient gene therapy remains a significant challenge. This study reports the design, synthesis, and evaluation of a novel multifunctional polypeptide-based nanoconjugate that addresses this gap using sequential delivery, combining mitochondrial targeting and nonviral gene therapy. We engineered a poly-l-ornithine-based, polyethylene glycol-modified carrier and introduced a novel custom-designed trivalent compound (TRV3) into the structure. TRV3, conjugated to the polypeptide carrier via a redox-sensitive disulfide linker, incorporates the well-described triphenylphosphonium moiety (TPP) for mitochondrial targeting and a Cy5 fluorophore as a model drug. The resulting nanoconjugate (C-TRV3-A) demonstrated efficient endosomal escape and mitochondrial localization. Leveraging the endosomolytic properties of C-TRV3-A, we explored its potential as a nonviral vector for gene therapy. After optimizing formulation stability using a VLC-3 anionic polypeptide coating, we developed plasmid DNA polyplexes that exhibited enhanced stability and transfection efficiency in basic and advanced triple-negative breast cancer cell culture models. This multifunctional polypeptide-based nanoconjugate represents a significant advance in the field, offering a chemically versatile platform for simultaneous subcellular targeting and gene delivery that may be used in targeted cancer treatments, among other pathologies.Fil: Pegoraro, Camilla. Príncipe Felipe Research Center; EspañaFil: Masiá Sanchis, Esther. Instituto de Salud Carlos III; España. Príncipe Felipe Research Center; EspañaFil: Dordevic, Snezana. No especifíca;Fil: Dolz Pérez, Irene. No especifíca;Fil: Huck Iriart, Cristián. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Instituto de Tecnologias Emergentes y Ciencias Aplicadas. - Universidad Nacional de San Martin. Instituto de Tecnologias Emergentes y Ciencias Aplicadas.; ArgentinaFil: Herrera, Lidia. No especifíca;Fil: Esteban Pérez, Sergio. No especifíca;Fil: Conejos Sanchez, Inmaculada. Instituto de Salud Carlos III; EspañaFil: Vicent, María J.. Instituto de Salud Carlos III; EspañaAmerican Chemical Society2025-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/276539Pegoraro, Camilla; Masiá Sanchis, Esther; Dordevic, Snezana; Dolz Pérez, Irene; Huck Iriart, Cristián; et al.; Multifunctional Polypeptide-Based Nanoconjugates for Targeted Mitochondrial Delivery and Nonviral Gene Therapy; American Chemical Society; Chemistry Of Materials; 37; 4; 2-2025; 1457-14670897-4756CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acs.chemmater.4c02742info:eu-repo/semantics/altIdentifier/doi/10.1021/acs.chemmater.4c02742info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-12-23T13:36:03Zoai:ri.conicet.gov.ar:11336/276539instacron: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:34982025-12-23 13:36:03.83CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Multifunctional Polypeptide-Based Nanoconjugates for Targeted Mitochondrial Delivery and Nonviral Gene Therapy
title Multifunctional Polypeptide-Based Nanoconjugates for Targeted Mitochondrial Delivery and Nonviral Gene Therapy
spellingShingle Multifunctional Polypeptide-Based Nanoconjugates for Targeted Mitochondrial Delivery and Nonviral Gene Therapy
Pegoraro, Camilla
gene therapy
proline
polypeptide
drug delivery
title_short Multifunctional Polypeptide-Based Nanoconjugates for Targeted Mitochondrial Delivery and Nonviral Gene Therapy
title_full Multifunctional Polypeptide-Based Nanoconjugates for Targeted Mitochondrial Delivery and Nonviral Gene Therapy
title_fullStr Multifunctional Polypeptide-Based Nanoconjugates for Targeted Mitochondrial Delivery and Nonviral Gene Therapy
title_full_unstemmed Multifunctional Polypeptide-Based Nanoconjugates for Targeted Mitochondrial Delivery and Nonviral Gene Therapy
title_sort Multifunctional Polypeptide-Based Nanoconjugates for Targeted Mitochondrial Delivery and Nonviral Gene Therapy
dc.creator.none.fl_str_mv Pegoraro, Camilla
Masiá Sanchis, Esther
Dordevic, Snezana
Dolz Pérez, Irene
Huck Iriart, Cristián
Herrera, Lidia
Esteban Pérez, Sergio
Conejos Sanchez, Inmaculada
Vicent, María J.
author Pegoraro, Camilla
author_facet Pegoraro, Camilla
Masiá Sanchis, Esther
Dordevic, Snezana
Dolz Pérez, Irene
Huck Iriart, Cristián
Herrera, Lidia
Esteban Pérez, Sergio
Conejos Sanchez, Inmaculada
Vicent, María J.
author_role author
author2 Masiá Sanchis, Esther
Dordevic, Snezana
Dolz Pérez, Irene
Huck Iriart, Cristián
Herrera, Lidia
Esteban Pérez, Sergio
Conejos Sanchez, Inmaculada
Vicent, María J.
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv gene therapy
proline
polypeptide
drug delivery
topic gene therapy
proline
polypeptide
drug delivery
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Despite recent advances in nanomedicine, developing multifunctional nanocarriers capable of targeted subcellular delivery and efficient gene therapy remains a significant challenge. This study reports the design, synthesis, and evaluation of a novel multifunctional polypeptide-based nanoconjugate that addresses this gap using sequential delivery, combining mitochondrial targeting and nonviral gene therapy. We engineered a poly-l-ornithine-based, polyethylene glycol-modified carrier and introduced a novel custom-designed trivalent compound (TRV3) into the structure. TRV3, conjugated to the polypeptide carrier via a redox-sensitive disulfide linker, incorporates the well-described triphenylphosphonium moiety (TPP) for mitochondrial targeting and a Cy5 fluorophore as a model drug. The resulting nanoconjugate (C-TRV3-A) demonstrated efficient endosomal escape and mitochondrial localization. Leveraging the endosomolytic properties of C-TRV3-A, we explored its potential as a nonviral vector for gene therapy. After optimizing formulation stability using a VLC-3 anionic polypeptide coating, we developed plasmid DNA polyplexes that exhibited enhanced stability and transfection efficiency in basic and advanced triple-negative breast cancer cell culture models. This multifunctional polypeptide-based nanoconjugate represents a significant advance in the field, offering a chemically versatile platform for simultaneous subcellular targeting and gene delivery that may be used in targeted cancer treatments, among other pathologies.
Fil: Pegoraro, Camilla. Príncipe Felipe Research Center; España
Fil: Masiá Sanchis, Esther. Instituto de Salud Carlos III; España. Príncipe Felipe Research Center; España
Fil: Dordevic, Snezana. No especifíca;
Fil: Dolz Pérez, Irene. No especifíca;
Fil: Huck Iriart, Cristián. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Instituto de Tecnologias Emergentes y Ciencias Aplicadas. - Universidad Nacional de San Martin. Instituto de Tecnologias Emergentes y Ciencias Aplicadas.; Argentina
Fil: Herrera, Lidia. No especifíca;
Fil: Esteban Pérez, Sergio. No especifíca;
Fil: Conejos Sanchez, Inmaculada. Instituto de Salud Carlos III; España
Fil: Vicent, María J.. Instituto de Salud Carlos III; España
description Despite recent advances in nanomedicine, developing multifunctional nanocarriers capable of targeted subcellular delivery and efficient gene therapy remains a significant challenge. This study reports the design, synthesis, and evaluation of a novel multifunctional polypeptide-based nanoconjugate that addresses this gap using sequential delivery, combining mitochondrial targeting and nonviral gene therapy. We engineered a poly-l-ornithine-based, polyethylene glycol-modified carrier and introduced a novel custom-designed trivalent compound (TRV3) into the structure. TRV3, conjugated to the polypeptide carrier via a redox-sensitive disulfide linker, incorporates the well-described triphenylphosphonium moiety (TPP) for mitochondrial targeting and a Cy5 fluorophore as a model drug. The resulting nanoconjugate (C-TRV3-A) demonstrated efficient endosomal escape and mitochondrial localization. Leveraging the endosomolytic properties of C-TRV3-A, we explored its potential as a nonviral vector for gene therapy. After optimizing formulation stability using a VLC-3 anionic polypeptide coating, we developed plasmid DNA polyplexes that exhibited enhanced stability and transfection efficiency in basic and advanced triple-negative breast cancer cell culture models. This multifunctional polypeptide-based nanoconjugate represents a significant advance in the field, offering a chemically versatile platform for simultaneous subcellular targeting and gene delivery that may be used in targeted cancer treatments, among other pathologies.
publishDate 2025
dc.date.none.fl_str_mv 2025-02
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/11336/276539
Pegoraro, Camilla; Masiá Sanchis, Esther; Dordevic, Snezana; Dolz Pérez, Irene; Huck Iriart, Cristián; et al.; Multifunctional Polypeptide-Based Nanoconjugates for Targeted Mitochondrial Delivery and Nonviral Gene Therapy; American Chemical Society; Chemistry Of Materials; 37; 4; 2-2025; 1457-1467
0897-4756
CONICET Digital
CONICET
url http://hdl.handle.net/11336/276539
identifier_str_mv Pegoraro, Camilla; Masiá Sanchis, Esther; Dordevic, Snezana; Dolz Pérez, Irene; Huck Iriart, Cristián; et al.; Multifunctional Polypeptide-Based Nanoconjugates for Targeted Mitochondrial Delivery and Nonviral Gene Therapy; American Chemical Society; Chemistry Of Materials; 37; 4; 2-2025; 1457-1467
0897-4756
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://pubs.acs.org/doi/10.1021/acs.chemmater.4c02742
info:eu-repo/semantics/altIdentifier/doi/10.1021/acs.chemmater.4c02742
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
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 12.952241

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