ArticleJournal of controlled release : official journal of the Controlled Release Society2022
Engineered ionizable lipid siRNA conjugates enhance endosomal escape but induce toxicity in vivo.
Article in Journal of controlled release : official journal of the Controlled Release Society, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 38 citations in OpenAlex.
- Investigating theBioconjugate chemistry · 2026Article
- Designed Liquid Crystalline Nanoassemblies From Clinically Validated Polyunsaturated Lipids for Combined Antioxidant, Anti-Apoptotic, and Neurotrophic Treatments.Advanced healthcare materials · 2026Article
- Decoding Undesirable Inflammatory Responses of Nucleic Acid-Delivering Lipid Nanoparticles.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Liposomal Nanoparticulate Drug Delivery Systems: Strategies to Destabilize Biological Membranes at the Target Tissue.International journal of nanomedicine · 2026Review
- Small Interfering RNA Carriers for Oncotherapy: A Preclinical Overview.Pharmaceutics · 2025Review
- Cleavable Hydrophobic Anchors Optimize Immunomodulatory Effects of Oligonucleotides.Journal of the American Chemical Society · 2025Article
- Artificial Intelligence-Driven Strategies for Targeted Delivery and Enhanced Stability of RNA-Based Lipid Nanoparticle Cancer Vaccines.Pharmaceutics · 2025Review
- Small nucleic acid drugs-the dawn of functional cure of chronic hepatitis B.Frontiers in pharmacology · 2025Review
- Structuring lipid nanoparticles, DNA, and protein corona into stealth bionanoarchitectures for in vivo gene delivery.Nature communications · 2024Article
- Development of mRNA Lipid Nanoparticles: Targeting and Therapeutic Aspects.International journal of molecular sciences · 2024Review
- RNAi-based drug design: considerations and future directions.Nature reviews. Drug discovery · 2024Review
- Recent trends in the delivery of RNA drugs: Beyond the liver, more than vaccine.European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V · 2024Review
- Mechanistic insights into endosomal escape by sodium oleate-modified liposomes.Beilstein journal of nanotechnology · 2024Article
- Increased Bone Marrow Uptake and Accumulation of Very-Late Antigen-4 Targeted Lipid Nanoparticles.Pharmaceutics · 2023Article
- Monitoring theAsian journal of pharmaceutical sciences · 2023Article
- Nucleic Acid Delivery to the Vascular Endothelium.Molecular pharmaceutics · 2022Review
- siRNA Functionalized Lipid Nanoparticles (LNPs) in Management of Diseases.Pharmaceutics · 2022Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Lipid conjugation supports delivery of small interfering RNAs (siRNAs) to extrahepatic tissues, expanding the therapeutic potential of siRNAs beyond liver indications. However, siRNA silencing efficacy in extrahepatic tissues remains inferior to that routinely achieved in liver, partially due to the low rate of endosomal escape following siRNA internalization. Improving siRNA endosomal release into cytoplasm is crucial to improving efficacy of lipid-conjugated siRNAs. Given the ability of ionizable lipids to enhance endosomal escape in a context of lipid nanoparticles (LNP), here, we provide the first report on the effect of an ionizable lipid conjugate on siRNA endosomal escape, tissue distribution, efficacy, and toxicity in vivo. After developing a synthetic route to covalently attach the ionizable lipid, DLin-MC3-DMA, to siRNAs, we demonstrate that DLin-MC3-DMA enhances endosomal escape in cell culture without compromising siRNA efficacy. In mice, DLin-MC3-DMA conjugated siRNAs exhibit a similar overall tissue distribution profile to the similarly hydrophobic cholesterol-conjugated siRNA. However, only DLin-MC3-DMA conjugated siRNAs accumulated in vascular compartments, suggesting an effect of conjugate structure on intratissue distribution. Interestingly, we observed non-specific modulation of gene expression in tissues with high accumulation of DLin-MC3-DMA siRNAs (>20 pmol/mg of tissue) while limited non-specific gene modulation has been observed in tissues with lower siRNA accumulation. These findings suggest modulating the nature of the conjugate is a promising strategy to alter siRNA intratissue and intracellular trafficking. Fine-tuning the nature of the conjugate to optimize endosomal escape while minimizing toxicity will be critical for the progression of therapeutic siRNA applications beyond the liver.
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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.