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Small Interfering RNA
The discovery of RNA interference (RNAi) and the roles that short interfering RNA (siRNA) and micro-RNA (miRNA) play in directing the reversible silencing of genes has enabled the creation of a whole new class of RNA therapeutics to target disease-causing genes that may be otherwise undruggable.
RNAi therapeutics currently being developed are poised to revolutionize:
Cancer treatments
Rare genetic disease treatments
Immunotherapy
Small RNA requires a delivery vehicle to protect against nucleases and to facilitate cellular uptake and release into the cytoplasm. Nanoparticles effectively solve several challenges facing small RNA delivery for basic research and drug development:
• Protection from nucleases
• Delivery and release into the cytoplasm
• Laborious and time-consuming viral packaging
• Safety concerns with viral vectors
• Toxicity with other delivery methods
• A
single approach for RNA delivery for all stages of research and drug development
Nanoparticle formulations can be prepared on demand in seconds with NanoAssemblr® technology.
Overcome Challenges in Small RNA Delivery
Several nanoparticle formulations are being explored to package and deliver siRNA including:
Liposomes
Polymer NPs and Micelles
LNPs
Among these, nucleic acid-LNPs are the most clinically advanced. The first RNAi drug slated for approval (Patisiran) uses LNPs to deliver siRNA. There are however challenges to producing siRNA-loaded nanoparticles that NanoAssemblr® technology addresses:
| Challenges with Conventional Methods | Benefits of NanoAssemblr® Technology | |
| Significant batch-to-batch variability |  | Create highly reproducible siRNA lipid nanoparticles |
| Substantial material loss from low encapsulation efficiency | | Generate siRNA lipid nanoparticles with high encapsulation efficacy and transfection potency |
| A labor-intensive production process that is difficult to scale up or scale down | | Rapidly produce formulations for screening and optimization with a straightforward path to scale-up for clinical applications |
Highly Reproducible siRNA LNP Formulations
Particle size and PDI determined by dynamic light scattering of siRNA LNPs produced by 3 independent users on the NanoAssemblr® Benchtop demonstrating process consistency.
High Encapsulation Efficiency and Potency
Serum levels of Factor VII protein in mice following i.v. injection of siRNA-LNPs shows a dose-dependent response. At RNA doses of 1 mg/kg over 90% knockdown was achieved for LNPs made
on the NanoAssemblr® Benchtop, Blaze,
and GMP System.Straightforward to Scale Production
Consistent results for size & PDI of siRNA LNPs achieved across the NanoAssemblr® Platform.
Size & PDI were determined by DLS from triplicate formulations. The composition was determined by HPLC.
1) An organic solvent containing dissolved lipids and an aqueous solution containing nucleic acids are injected into the two inlet channels of the NanoAssemblr® cartridge.
2) Under laminar flow, the two solutions do not immediately mix, but microscopic features engineered into the channel cause the two fluids to intermingle in a controlled and reproducible way.
3) Within a millisecond, the two fluids are completely mixed, causing a change in solvent polarity that triggers the self-assembly of lipid nanoparticles loaded with nucleic acids.
4) Changing the speed and ratio of fluid injection controls the size of the lipid nanoparticles.
5) Lipid nanoparticles mimic low-density lipoproteins, which allows them to be taken up by an endogenous cellular transport pathway to deliver nucleic acids to cells.
6) Using pH-sensitive lipids allow lipid nanoparticles to release encapsulated nucleic acids into the cytoplasm when vesicle pH decreases.
siRNA Resources
Application Note
March 15, 2022
Publication - Summary
May 18, 2019
Annals of Hematology
Publication - Summary
April 04, 2019
The Journal of Neuroscience
Application Note
January 02, 2018
Poster
February 09, 2022
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