Systemic Gene Silencing in Primary T Lymphocytes Using Targeted Lipid Nanoparticles


Authors: Ramishetti S, Kedmi R, Goldsmith M, Leonard F, Sprague AG, Godin B, Gozin M, Cullis PR, Dykxhoorn DM, Peer D

Journal: ACS Nano

DOI: 10.1021/acsnano.5b02796

Publication - Abstract

June 10, 2015

Abstract:

Modulating T cell function by down-regulating specific genes using RNA interference (RNAi) holds tremendous potential in advancing targeted therapies in many immune-related disorders including cancer, inflammation, autoimmunity, and viral infections. Hematopoietic cells, in general, and primary Tlymphocytes, in particular, are notoriously hard to transfect with small interfering RNAs (siRNAs). Herein, we describe a novel strategy to specifically deliver siRNAs to murine CD4(+) T cells using targeted lipid nanoparticles (tLNPs). To increase the efficacy of siRNA delivery, these tLNPs have been formulated with several lipids designed to improve the stability and efficacy of siRNA delivery. The tLNPs were surface-functionalized with anti-CD4 monoclonal antibody to permit delivery of the siRNAs specifically to CD4(+) T lymphocytes. Ex vivo, tLNPs demonstrated specificity by targeting only primary CD4(+) T lymphocytesand no other cell types. Systemic intravenous administration of these particles led to efficient binding and uptake into CD4(+) T lymphocytes in several anatomical sites including the spleen, inguinal lymph nodes, blood, and the bone marrow. Silencing by tLNPs occurs in a subset of circulating and resting CD4(+) T lymphocytes. Interestingly, we show that tLNP internalization and not endosome escape is a fundamental event that takes place as early as 1 h after systemic administration and determines tLNPs’ efficacy. Taken together, these results suggest that tLNPs may open new avenues for the manipulation of Tcell functionality and may help to establish RNAi as a therapeutic modality in leukocyte-associated diseases.

Advanced Search

close
  • Publications
  • Application Notes
  • Posters
  • Workshops
  • Videos & Webinars
  • Blog Posts
Search

Browse by Category

  • Application
    • Diagnostic and Imaging
    • Genetic Medicine
    • Hematology
    • Metabolic Disorders
    • Neuroscience
    • Oncology
    • Skeletal Disorders
    • Targeted Drug Delivery
    • Vaccines
    • Other Applications
  • Formulation
    • Liposomes
    • Nucleic Acid Lipid Nanoparticles
    • Polymeric Nanoparticles
    • Other Formulations
  • Payload
    • DNA
    • microRNA
    • mRNA
    • siRNA
    • Small Molecule Drugs
    • Other Payloads


related content

Publication - Abstract

The discovery of RNA interference (RNAi) in mammalian cells has created a new class of therapeutics based on the reversible silencing of specific disease-causing genes.

Read More


Publication - Abstract

Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies

Dejanovic, B., Huntley, M. A., De Mazière, A., Meilandt, W. J., Wu, T., Srinivasan, K., . . . Sheng, M.

Synapse loss and Tau pathology are hallmarks of Alzheimer’s disease (AD) and other tauopathies, but how Tau pathology causes synapse loss is unclear. We used unbiased proteomic analysis of postsynaptic densities (PSDs) in Tau-P301S transgenic mice to identify Tau-dependent ...
Read More


Stay Informed

Sign up today to automatically receive new Precision NanoSystems application notes, conference posters, relevant science publications, and webinar invites.

MENU
X