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Published in Chad A. Mirkin, Spherical Nucleic Acids, 2020
Gokay Yamanluirt, Eric J. Berns, Albert Xue, Andrew Lee, Neda Bagheri, Milan Mrksich, Chad A. Mirkin
The oligonucleotide shell serves two roles. It facilitates cellular uptake and serves as the adjuvant, which activates the innate immune system in a sequence-specific manner [5]. The oligonucleotides used in the design of SNAs in the library varied in five ways: sequence, backbone chemistry, conjugation chemistry to the liposome, site of lipid functionalization and surface density of presentation by SNAs (albeit over a narrow range). We chose a CpG DNA oligonucleotide (ODN1826) known to activate mouse TLR9, as well as an inactive control where the CpG motif is inverted to GpC [11, 12]. TLR9 is an endosomal protein that recognizes unmethylated CpG oligonucleotides associated with bacteria and viruses [13]. To explore the importance of backbone composition, we synthesized linear oligonucleotides with either phosphodiester (PO) or phosphorothioate (PS) backbones, since phosphorothioate oligonucleotides are known to induce higher immune activation, but SNAs comprising phosphodiester backbones present activities comparable to phosphorothioate structures [5, 14]. We evaluated distinct strategies for conjugating oligonucleotides to the nanoparticles by preparing structures with cholesterol or DOPE, both of which insert into the liposomal cores and can be chemically attached to the 3′ or 5′ ends of the oligonucleotides.
Lipid-Based Nanoparticles for siRNA Delivery
Published in Yubing Xie, The Nanobiotechnology Handbook, 2012
Bo Yu, L. James Lee, Robert J. Lee
siRNAs may potentially cause problems by triggering a cytokine response, which stems from the recognition by toll-like receptors (TLRs) in cells of the innate immune system (Agrawal and Kandimalla 2004, Judge and MacLachlan 2008, Robbins et al. 2009). It is well-established that unmethylated CpG motifs are able to stimulate the immune system by the TLR9-driven pathway (Klinman 2004). Similarly, siRNAs can be recognized by TLR3 or TLR7/8 (Judge and MacLachlan 2008, Robbins et al. 2009). In addition to the TLRs, the helicases RIG-1 and Mda5 as well as protein kinase R play an important role in the recognition of siRNAs by the immune system. The majority of innate immune activation by siRNAs in vivo is mediated through TLR7/8 in immune cells. It was revealed that TLR7/8 binding is sequence specific, favoring GU-rich sequences (Judge et al. 2005, Judge and MacLachlan 2008, Robbins et al. 2009). Therefore, the recognition of siRNAs by TLR7/8 can be avoided by choosing sequences that are not recognized by these receptors. Additionally, TLR7/8-mediated recognition and immune stimulation by siRNA can be reduced by the 2′-O-methyl modification on the siRNA. In contrast, 2′-O-methylation of siRNA does not block TLR3 activation (Kleinman et al. 2008). Unlike TLR7/8, TLR3 is localized in both the cell surface and the endosome (Sioud 2008, Robbins et al. 2009, Semple et al. 2010). In a recent clinical trial of siRNA targeting vascular endothelial growth factor (VEGF), it was demonstrated that the observed decrease in vascularization was not a sequence- and target-dependent effect on angiogenesis, but rather a result of nonspecific activation of TLR3 (Kleinman et al. 2008). This finding highlighted another concern for the safe use of siRNAs-based therapeutics in clinic (Judge and MacLachlan 2008, Robbins et al. 2009).
Inhibitory effect of particulate matter on toll-like receptor 9 stimulated dendritic cells by downregulating mitogen-activated protein kinase and NF-κB pathway
Published in Journal of Toxicology and Environmental Health, Part A, 2020
Madeeha Arooj, Irshad Ali, Hee Kyoung Kang, Jin Won Hyun, Young-Sang Koh
Within the endoplasmic reticulum and endosomes, bacterial DNA sequences consisting of unmethylated CpG activate toll-like receptor 9 (TLR9). TLR9 plays a crucial role in defense against bacterial and viral infections. Several investigators noted that TLR9 was responsible for the induction of Th1-based immune response and proliferation of B-cells (Fields, Fitch, and Gajewaski 1996; Huang and Yang 2010). At present the effects of PM2.5 on the innate immune system are not fully understood. Since it is well known that fine PM2.5 was found to enhance inflammatory reactions in mice (Castaneda et al. 2017) it was of interest to examine the influence of PM2.5 on the innate immune system and the underlying mechanisms.