Highly efficient CD4+ T cell targeting and genetic recombination using engineered CD4+ cell-homing mRNA-LNPs.
Animals
CD4-Positive T-Lymphocytes
/ immunology
COVID-19
/ immunology
COVID-19 Vaccines
/ immunology
Humans
Immunotherapy
/ methods
Lipids
/ genetics
Lymph Nodes
/ immunology
Mice
Mice, Inbred C57BL
Nanoparticles
/ administration & dosage
RNA, Messenger
/ genetics
Recombination, Genetic
/ genetics
SARS-CoV-2
/ immunology
Spleen
/ immunology
Transfection
/ methods
LNP
T cell
genetic recombination
lipid nanoparticle
mRNA
targeted mRNA delivery
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
03 11 2021
03 11 2021
Historique:
received:
27
11
2020
revised:
30
04
2021
accepted:
01
06
2021
pubmed:
7
6
2021
medline:
18
11
2021
entrez:
6
6
2021
Statut:
ppublish
Résumé
Nucleoside-modified messenger RNA (mRNA)-lipid nanoparticles (LNPs) are the basis for the first two EUA (Emergency Use Authorization) COVID-19 vaccines. The use of nucleoside-modified mRNA as a pharmacological agent opens immense opportunities for therapeutic, prophylactic and diagnostic molecular interventions. In particular, mRNA-based drugs may specifically modulate immune cells, such as T lymphocytes, for immunotherapy of oncologic, infectious and other conditions. The key challenge, however, is that T cells are notoriously resistant to transfection by exogenous mRNA. Here, we report that conjugating CD4 antibody to LNPs enables specific targeting and mRNA interventions to CD4+ cells, including T cells. After systemic injection in mice, CD4-targeted radiolabeled mRNA-LNPs accumulated in spleen, providing ∼30-fold higher signal of reporter mRNA in T cells isolated from spleen as compared with non-targeted mRNA-LNPs. Intravenous injection of CD4-targeted LNPs loaded with Cre recombinase-encoding mRNA provided specific dose-dependent loxP-mediated genetic recombination, resulting in reporter gene expression in about 60% and 40% of CD4+ T cells in spleen and lymph nodes, respectively. T cell phenotyping showed uniform transfection of T cell subpopulations, with no variability in uptake of CD4-targeted mRNA-LNPs in naive, central memory, and effector cells. The specific and efficient targeting and transfection of mRNA to T cells established in this study provides a platform technology for immunotherapy of devastating conditions and HIV cure.
Identifiants
pubmed: 34091054
pii: S1525-0016(21)00310-5
doi: 10.1016/j.ymthe.2021.06.004
pmc: PMC8571164
pii:
doi:
Substances chimiques
COVID-19 Vaccines
0
Lipids
0
RNA, Messenger
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3293-3304Subventions
Organisme : NIAID NIH HHS
ID : P30 AI045008
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI124429
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL134839
Pays : United States
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests H.P., I.T., N.P., V.R.M., and D.W. are inventors on a patent filed on some aspects of this work. Those interests have been fully disclosed to the University of Pennsylvania. All other authors declare no competing interests.
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