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Bioengineered baculovirus-derived extracellular vesicles loaded with of γ-carboxylated Gla-rich protein : dual modulation of inflammation and vascular calcification

2026-07Contributo em revista Acesso aberto
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datacite.subject.fosCiências Médicas::Biotecnologia Médica
dc.contributor.authorViegas, Carla
dc.contributor.authorPichard, Simon
dc.contributor.authorCarreira, Joana
dc.contributor.authorOva, Adélia
dc.contributor.authorTroffer-Charlier, Nathalie
dc.contributor.authorMaia, Teresa M.
dc.contributor.authorEdelweiss, Evelina
dc.contributor.authorMacedo, Anjos L.
dc.contributor.authorMatos, António
dc.contributor.authorFaria, Tiago Q.
dc.contributor.authorCalado, Sofia M.
dc.contributor.authorMonico, Carina
dc.contributor.authorDevos, Simon
dc.contributor.authorImpens, Francis
dc.contributor.authorSchaeffer-Reiss, Christine
dc.contributor.authorCianférani, Sarah
dc.contributor.authorPeixoto, Cristina
dc.contributor.authorPoterszman, Arnaud
dc.contributor.authorSimes, Dina
dc.date.accessioned2026-06-02T11:18:41Z
dc.date.available2026-06-02T11:18:41Z
dc.date.issued2026-07
dc.description.abstractChronic inflammation and ectopic calcification are interrelated processes driving major chronic inflammatory diseases such as cardiovascular and chronic kidney diseases. Gla-rich protein (GRP), a vitamin K–dependent protein (VKDP) with dual anti-inflammatory and anti-calcific properties, has emerged as a promising therapeutic molecule. However, its biomedical development has been limited by difficulties in producing the γ-carboxylated (cGRP) form and by its poor solubility at physiological pH, constraining formulation and delivery. To address these challenges, we established a baculovirus expression vector system (BEVS) designed to couple GRP post-translational maturation with its secretion in extracellular vesicles (EVs). Co-expression of GRP with γ-glutamyl carboxylase (GGCX), vitamin K epoxide reductase (VKOR), and the convertase Furin enabled efficient γ-carboxylation, propeptide removal, and secretion of mature cGRP. GGCX and VKOR were essential for γ-carboxylation, while Furin mediated propeptide processing. EVs were isolated by differential ultracentrifugation into 30 K and 100 K fractions and characterized by NTA, TEM, Western blot, ELISA, and proteomics. All vesicles displayed physical and molecular features resembling mammalian EVs, including canonical EV markers and distinct proteomic profiles, with GRP, GGCX, VKOR, and Furin preferentially enriched in the 30 K population. Functional assays demonstrated that the resulting EVs associated with human THP-1 macrophages and vascular smooth muscle cells (VSMCs) without inducing cytotoxicity, and both cGRP-EVs and uncarboxylated GRP-EVs reduced pro-inflammatory cytokine release while exerting dual anti-inflammatory and anti-mineralizing effects. This study establishes the first bioengineered platform capable of generating functional γ-carboxylated GRP and its vesicular formulation, providing a dual innovation for VKDP research and therapeutic biomaterial development.eng
dc.identifier.citationCarla Viegas, Simon Pichard, Joana Carreira, Adélia Ova, Nathalie Troffer-Charlier, Teresa M. Maia, Evelina Edelweiss, Anjos L. Macedo, António Matos, Tiago Q. Faria, Sofia M. Calado, Carina Monico, Simon Devos, Francis Impens, Christine Schaeffer-Reiss, Sarah Cianférani, Cristina Peixoto, Arnaud Poterszman, Dina Simes, Bioengineered baculovirus-derived extracellular vesicles loaded with of γ-carboxylated Gla-rich protein: Dual modulation of inflammation and vascular calcification, Biomaterials Advances, Volume 184, 2026, 214833, https://doi.org/10.1016/j.bioadv.2026.214833
dc.identifier.doi10.1016/j.bioadv.2026.214833
dc.identifier.issn2772-9508
dc.identifier.urihttp://hdl.handle.net/10400.26/63498
dc.language.isoeng
dc.peerreviewedyes
dc.publisherElsevier
dc.relation.hasversionhttps://doi.org/10.1016/j.bioadv.2026.214833
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectExtracellular vesicles
dc.subjectGla-rich protein
dc.subjectγ-carboxylation
dc.subjectBaculovirus expression vector system
dc.subjectVitamin K–dependent proteins
dc.subjectInflammation
dc.subjectCalcification
dc.titleBioengineered baculovirus-derived extracellular vesicles loaded with of γ-carboxylated Gla-rich protein : dual modulation of inflammation and vascular calcificationeng
dc.typecontribution to journal
dspace.entity.typePublication
oaire.citation.startPage214833
oaire.citation.titleBiomaterials Advances
oaire.citation.volume184
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85

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