Highly efficient CD4+ T cell targeting and genetic recombination using engineered CD4+ cell-homing mRNA-LNPs

Jun 6, 2021Molecular therapy : the journal of the American Society of Gene Therapy

Highly efficient targeting and genetic editing of helper T cells using engineered mRNA nanoparticles that home to these cells

AI simplified

mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

CD4-targeted mRNA-lipid nanoparticles achieved a 30-fold higher signal of reporter mRNA in T cells compared to non-targeted nanoparticles.

Conjugating CD4 antibody to lipid nanoparticles enables targeted delivery of mRNA to CD4+ cells.
After intravenous injection in mice, targeted mRNA-lipid nanoparticles showed significant accumulation in the spleen.
Specific dose-dependent genetic recombination was observed in about 60% of CD4+ T cells in the spleen and 40% in lymph nodes.
Uniform transfection across different T cell subpopulations was noted, with consistent uptake of the targeted mRNA-lipid nanoparticles.

AI simplified

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.

Full Text

We can’t show the full text here under this license. Use the link below to read it at the source.

View full text (XML) ↗View full text ↗

Highly efficient CD4+ T cell targeting and genetic recombination using engineered CD4+ cell-homing mRNA-LNPs

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the mrna technology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the mrna technology brief