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Immunogenicity Testing of Lipidoids In Vitro and In Silico: Modulating Lipidoid-Mediated TLR4 Activation by
Anne Marit de Groot1, Kaushik Thanki2, Monique Gangloff3
1Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, the Netherlands.
Molecular Therapy. Nucleic Acids
|June 3, 2018
Summary
Small interfering RNA (siRNA) therapeutics show promise, but delivery is key. Lipid-polymer hybrid nanoparticles (LPNs) improve siRNA delivery, yet cationic lipids like lipidoids can activate Toll-like receptor 4 (TLR4), which is mitigated by formulation.
Area of Science:
- Biotechnology
- Nanomedicine
- Immunology
Background:
- Small interfering RNA (siRNA) holds potential for antiviral and anti-inflammatory therapies.
- Non-viral nanoparticulate systems are crucial for delivering siRNA into target cells.
- Lipid-polymer hybrid nanoparticles (LPNs) enhance siRNA delivery compared to traditional formulations.
Purpose of the Study:
- To investigate the innate immune-modulating properties of cationic lipids used in siRNA delivery systems.
- To compare the immune activation potential of lipidoids versus dioleoyltrimethylammoniumpropane (DOTAP).
- To assess the impact of formulation on lipidoid-mediated immune responses.
Main Methods:
- In vitro testing of lipidoids and DOTAP for activation of human Toll-like receptors (TLRs 2, 3, 7, 9).
- Assessment of TLR4 activation by lipidoids and DOTAP using murine antigen-presenting cells.
- In silico analysis using a crystal structure-based prediction model.
- Evaluation of TLR4 activation in different lipidoid formulations (lipoplexes, stable nucleic acid lipid particles, LPNs).
Main Results:
- Neither lipidoids nor DOTAP activated human TLRs 2, 3, 7, or 9.
- Lipidoids, unlike DOTAP, strongly activated TLR4 and murine antigen-presenting cells in vitro.
- In silico modeling confirmed the TLR4 agonistic activity of lipidoids.
- TLR4 activation was observed with lipidoids in lipoplexes and stable nucleic acid lipid particles but was abrogated in LPNs.
- PLGA incorporation into LPNs effectively suppressed lipidoid-induced TLR4 activation.
Conclusions:
- Cationic lipidoids, while effective for siRNA delivery, possess TLR4 agonistic properties.
- Formulation design, specifically the combination with PLGA in LPNs, can mitigate unwanted TLR4 activation.
- Optimization of LPN formulations is critical for safe and effective siRNA therapeutics, balancing delivery efficiency with immune response modulation.
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