Cationic lipids activate intracellular signaling pathways

Immune responses of therapeutic lipid nanoparticles

“…Activation of TLR4 also triggered dynamindependent endocytosis [15] , which resulted in activation of interferon regulatory factor 3 (IRF-3) and expression of interferon-induced molecules (IFN-β , IP-10) [14] . These responses were not observed with other cationic lipids, including the TAP and EPC families, and dimethyldioctadecylammonium (bromide salt) (DDAB) [8,14] .…”

“…Tanaka et al [14] synthesized a new lipid DiC14-amidine and demonstrated that the DiC14-amidine liposomes activated the nuclear factor-κ B (NF-κ B) pathway in mouse and human DCs. They discovered that DiC14-amidine was recognized by the Toll-like receptor 4 (TLR4) and its co-receptors MD2 and CD14, inducing a cascade that led to activation of mitogen-activated protein kinases (MAPKs) and NF-κ B and expression of several proinflammatory cytokines (IL-6, IL-12, TNF-α ) and co-stimulatory molecules (CD80/ CD86) [8,14] . Activation of TLR4 also triggered dynamindependent endocytosis [15] , which resulted in activation of interferon regulatory factor 3 (IRF-3) and expression of interferon-induced molecules (IFN-β , IP-10) [14] .…”

“…Yan et al [13] reported that DC stimulation by optimal cationic liposomes composed of DOTAP (1,2-dioleyl-3-trimethylammonium propane) was mediated by reactive oxygen species (ROS), which activated extracellular signal-regulated kinase (ERK) and p38, and the downstream cytokines/chemokines, such as interleukin-12 (IL-12) and chemokine (C-C motif) ligand 2 (CCL2). Different cationic lipids could induce different immune responses via distinguished mechanisms [8] . Tanaka et al [14] synthesized a new lipid DiC14-amidine and demonstrated that the DiC14-amidine liposomes activated the nuclear factor-κ B (NF-κ B) pathway in mouse and human DCs.…”

“…Cationic liposomes are commonly used as a non-viral gene delivery system and as an immunoadjuvant for vaccines [8] . The Huang laboratory has demonstrated that s.c. injected cationic liposomes ( ∼ 100 nm) were largely taken up by dendritic cells (DCs) [9 -13] .…”

Evading innate immunity in nonviral mRNA delivery: don’t shoot the messenger

“…As for the protamine-RNA complexes, also DOTAP and PEI RNA formulations were shown to be detected by TLR-7 and TLR-8 [26,30]. Furthermore, Lonez et al conclude that multiple cationic lipids, such as stearylamine-liposomes and Lipofectamine, in itself activate intracellular immune pathways, independent of mRNA complexation, resulting in the induction of several pro-apoptotic and pro-inflammatory signaling molecules [76]. The activated immune profile will additionally depend on the particle size, as it has been shown that the immune system distinguishes nanometric and micrometric structures in order to adapt the response to viral or bacterial/fungal organisms [77].…”