ArticleMolecular therapy : the journal of the American Society of Gene Therapy2016
The Niemann-Pick C1 Inhibitor NP3.47 Enhances Gene Silencing Potency of Lipid Nanoparticles Containing siRNA.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 48 citations in OpenAlex.
- Rational design of lipid nanoparticles for enabling gene therapies.Molecular therapy. Methods & clinical development · 2025Review
- Endosomal Escape and Nuclear Localization: Critical Barriers for Therapeutic Nucleic Acids.Molecules (Basel, Switzerland) · 2024Review
- Current landscape of mRNA technologies and delivery systems for new modality therapeutics.Journal of biomedical science · 2024Review
- Novel Efficient Lipid-Based Delivery Systems Enable a Delayed Uptake and Sustained Expression of mRNA in Human Cells and Mouse Tissues.Pharmaceutics · 2024Article
- RNA-Based Vaccines and Therapeutics Against Intracellular Pathogens.Methods in molecular biology (Clifton, N.J.) · 2024Review
- Article
- siRNA Functionalized Lipid Nanoparticles (LNPs) in Management of Diseases.Pharmaceutics · 2022Review
- Hydroxycholesterol substitution in ionizable lipid nanoparticles for mRNA delivery to T cells.Journal of controlled release : official journal of the Controlled Release Society · 2022Article
- Delivery of Oligonucleotide Therapeutics: Chemical Modifications, Lipid Nanoparticles, and Extracellular Vesicles.ACS nano · 2021Review
- Extracellular vesicles mediated exocytosis of antisense peptide nucleic acids.Molecular therapy. Nucleic acids · 2021Article
- Recent Developments in Delivery of MicroRNAs Utilizing Nanosystems for Metabolic Syndrome Therapy.International journal of molecular sciences · 2021Review
- Lipid-Based Nanoparticles in the Clinic and Clinical Trials: From Cancer Nanomedicine to COVID-19 Vaccines.Vaccines · 2021Review
- Nanoscopy for endosomal escape quantification.Nanoscale advances · 2021Review
- Viral Mimicry as a Design Template for Nucleic Acid Nanocarriers.Frontiers in chemistry · 2021Review
- Cellular Targeting of Oligonucleotides by Conjugation with Small Molecules.Molecules (Basel, Switzerland) · 2020Review
- Recent advances in siRNA delivery mediated by lipid-based nanoparticles.Advanced drug delivery reviews · 2020Review
- Endocytic Profiling of Cancer Cell Models Reveals Critical Factors Influencing LNP-Mediated mRNA Delivery and Protein Expression.Molecular therapy : the journal of the American Society of Gene Therapy · 2019Article
- Using macropinocytosis for intracellular delivery of therapeutic nucleic acids to tumour cells.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2019Review
- Intracellular Trafficking and Endosomal Release of Oligonucleotides: What We Know and What We Don't.Nucleic acid therapeutics · 2018Review
- Recent Advances in Nanoparticle-Based Cancer Drug and Gene Delivery.Advances in cancer research · 2018Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The therapeutic applications of lipid nanoparticle (LNP) formulations of small interfering RNA (siRNA), are hampered by inefficient delivery of encapsulated siRNA to the cytoplasm following endocytosis. Recent work has shown that up to 70% of endocytosed LNP-siRNA particles are recycled to the extracellular medium and thus cannot contribute to gene silencing. Niemann-Pick type C1 (NPC1) is a late endosomal/lysosomal membrane protein required for efficient extracellular recycling of endosomal contents. Here we assess the influence of NP3.47, a putative small molecule inhibitor of NPC1, on the gene silencing potency of LNP-siRNA systems in vitro. Intracellular uptake and colocalization studies revealed that the presence of NP3.47 caused threefold or higher increases in accumulation of LNP-siRNA in late endosomes/lysosomes as compared with controls in a variety of cell lines. The gene silencing potency of LNP siRNA was enhanced up to fourfold in the presence of NP3.47. Mechanisms of action studies are consistent with the proposal that NP3.47 acts to inhibit NPC1. Our findings suggest that the pharmacological inhibition of NPC1 is an attractive strategy to enhance the therapeutic efficacy of LNP-siRNA by trapping LNP-siRNA in late endosomes, thereby increasing opportunities for endosomal escape.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.