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Cited by 61Graphene and Nanomaterials ApplicationsLiver physiology and pathologyNanoparticle-Based Drug Delivery

Graphene–Dendrimer Nanostars for Targeted Macrophage Overexpression of Metalloproteinase 9 and Hepatic Fibrosis Precision Therapy

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Melgar-Lesmes, Pedro, Luquero, Aureli, Parra-Robert, Marina, Mora, Adriana, Ribera, Jordi, Edelman, Elazer R., Jiménez, Wladimiro·2018·Nano Letters
DOI 10.1021/acs.nanolett.8b02498PMC PMC6377857
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Abstract

Fibrosis contributes to ∼45% of all deaths in industrialized nations, but no direct antifibrotic therapeutic interventions exist to date. Graphene-based nanomaterials exhibit excellent versatility in electronics, and emerging trends exploit their properties for biomedical applications, especially for drug and gene delivery. We designed constructs of graphene nanostars linked to PAMAM-G5 dendrimer for the selective targeting and delivery of a plasmid expressing the collagenase metalloproteinase 9 under the CD11b promoter into inflammatory macrophages in cirrhotic livers. Graphene nanostars preferentially accumulated in inflammatory macrophages M1 in less than 3 h in a manner unaffected by covalent linkage to dendrimers. Dendrimer-graphene nanostars efficiently delivered the plasmid encoding for metalloproteinase 9 into macrophages, allowing the synthesis and secretion of the metalloproteinase to digest adjacent collagen fibers. In turn, metalloproteinase 9 overexpression promoted the macrophage switch from inflammatory M1 to pro-regenerative M2 in 3 days. This targeted gene therapy reduced selectively and locally the presence of collagen fibers in fibrotic tracts where inflammatory macrophages accumulated in cirrhotic mice without affecting the activation state of hepatic stellate cells. Overall, this treatment significantly reduced hepatic injury and improved liver restoration in mice with liver cirrhosis treated for 10 days. Graphene-dendrimer nanostars targeted the macrophage overexpression of metalloproteinase 9, selectively reducing hepatic fibrosis, and might be a good treatment for diseases associated with fibrosis and inflammatory macrophage accumulation.

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  • This MMP-9 gene-delivery approach selectively reduced collagen deposition in fibrotic regions enriched in inflammatory macrophages, while leaving HSC activation largely unaffected.

    “This approach selectively reduced collagen deposition in fibrotic regions enriched in inflammatory macrophages, while leaving HSC activation largely unaffected.”

    From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [97]

  • Targeted overexpression of MMP-9 in macrophages induced a phenotypic switch toward a pro-regenerative restorative state both in vitro and in vivo.

    “Although MMP-9 is typically upregulated during fibrogenesis, its targeted overexpression in macrophages induced a phenotypic switch toward a pro-regenerative restorative state both in vitro and in vivo.”

    From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [97]

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Authors
Melgar-Lesmes, P., Luquero, A., Parra-Robert, M., Mora, A., Ribera, J., Edelman, E. R., & Jiménez, W.
Affiliations
  • Institute for Medical Engineering and Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
  • Universitat de Barcelona (ES)
  • Biochemistry and Molecular Genetics Service, Hospital Clínic Universitari, IDIBAPS, CIBERehd, 170 Villarroel, 08036 Barcelona, Spain
  • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
  • Brigham and Women's Hospital (US)
ORCID
Venue
Nano Letters
Publisher
American Chemical Society (ACS)
Published
2018-08-10
Volume
18
Issue
9
Pages
5839-5845
ISSN
  • 1530-6984 (ISSN-L)
  • 1530-6992
DOI
10.1021/acs.nanolett.8b02498
PMC
PMC6377857
OpenAlex
W2885800282
Cited by
61
References
2
Citations by year
2026: 6 · 2025: 4 · 2024: 11 · 2023: 13 · 2022: 9 · 2021: 7 · 2020: 7 · 2019: 3 · 2018: 1
FWCI
1.80
Type
journal article
Language
en
Open access
Locations
  • Nano Letters (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
Funders
  • Ministerio de Econom?a y Competitividad (SAF2015-64126-R)
  • Ag?ncia de Gesti? d?Ajuts Universitaris i de Recerca (BP-00236)
  • Generalitat de Catalunya (PERIS SLT002/16/00341)
  • National Institute of General Medical Sciences (R01 GM 49039)
  • European Association for the Study of the Liver
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › Graphene and Nanomaterials Applications
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
PAMAM dendrimers, MMP-9, collagenase, liver fibrosis, liver cirrhosis, macrophage targeting, plasmid DNA delivery, gene therapy, antifibrotic therapy, collagen degradation, liver regeneration
MeSH terms
Animals, Graphite, Liver Cirrhosis, Macrophages, Mice, Inbred BALB C, Plasmids, Genetic Therapy, Up-Regulation, Gene Transfer Techniques, Matrix Metalloproteinase 9, Dendrimers, Mice, Nanoparticles

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