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Published in Chad A. Mirkin, Spherical Nucleic Acids, 2020
Aleksandar F. Radovic-Moreno, Natalia Chernyak, Christopher C. Mader, Subbarao Nallagatla, Richard S. Kang, Liangliang Hao, David A. Walker, Tiffany L. Halo, Timothy J. Merkel, Clayton H. Rische, Sagar Anantatmula, Merideth Burkhart, Chad A. Mirkin, Sergei M. Gryaznov
Immunomodulatory nucleic acids have extraordinary promise for treating disease, yet clinical progress has been limited by a lack of tools to safely increase activity in patients. Immunomodulatory nucleic acids act by agonizing or antagonizing endosomal toll-like receptors (TLR3, TLR7/8, and TLR9), proteins involved in innate immune signaling. Immunomodulatory spherical nucleic acids (SNAs) that stimulate (immunostimulatory, IS-SNA) or regulate (immunoregulatory, IR-SNA) immunity by engaging TLRs have been designed, synthesized, and characterized. Compared with free oligonucleotides, IS-SNAs exhibit up to 80-fold increases in potency, 700-fold higher antibody titers, 400-fold higher cellular responses to a model antigen, and improved treatment of mice with lymphomas. IR-SNAs exhibit up to eightfold increases in potency and 30% greater reduction in fibrosis score in mice with nonalcoholic steatohepatitis (NASH). Given the clinical potential of SNAs due to their potency, defined chemical nature, and good tolerability, SNAs are attractive new modalities for developing immunotherapies.
Immune Reactions in the Delivery of RNA Interference-Based Therapeutics: Mechanisms and Opportunities
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
Kaushik Thanki, Emily Falkenberg, Monique Gangloff, Camilla Foged
Chemical modification can also be harnessed to address immunostimulation, which is another key hurdle to RNAi therapy (Fig. 14.3, right). The innate immune system is activated when siRNA molecules are recognized by toll-like receptors (TLRs), e.g., TLR3, TLR7 and TLR8. The 2′-O-Me, 2′-F and phosphorothioate modifications discussed above are multifunctional in nature, because they also impede TLR recognition. Incorporation of as few as two 2′-O-Me nucleotides is sufficient to abrogate TLR recognition of an entire siRNA molecule [18]. Mechanistically, 2′ methyl groups act as competitive inhibitors of TLR7 thereby protecting them in trans [15]. Other modifications, which prevent immunostimulation in naturally occurring RNA molecules, can be incorporated in synthetic siRNAs to achieve a similar effect. These include incorporation of pseudouridine and N6-methylated-adenosine (Fig. 14.3), respectively, inhibiting binding to TLR7 and TLR3. Incorporation of N6-methyladenosine specifically evades immune stimulation by destabilizing the duplex structure, recognized by TLR3. However, pseudouridine and N6-methylated-adenosine modifications are utilized to a limited extent due to the success of other modifications, in particular 2′-O-Me [19]. Finally, 2′-deoxynucleotides (Fig. 14.3) have recently been reported to impede immune recognition, particularly dU and dT bases [20]. Unlike other modifications, this modification is exceptionally versatile with the possibility for incorporation in the entire passenger strand and the 5' end of the guide strand without affecting RNAi potency [21].
PM2.5 aggravates airway inflammation in asthmatic mice: activating NF-κB via MyD88 signaling pathway
Published in International Journal of Environmental Health Research, 2023
Lei Wang, Yanzhi Cui, Hu Liu, Jing Wu, Jie Li, Xiansheng Liu
PM2.5 produced by human factors such as fossil fuel burning contains many toxic chemicals. The identified components include sulfate (SO42-)/nitrate (NO3-), polycyclic aromatic hydrocarbons (PAHs), transition metals (e.g. Fe, Cu and Ni), microbial components (e.g. lipopolysaccharide [LPS] and β-glucan) (Martins et al. 2016). Toll-like receptors (TLRs) are natural immunosensors, and antigen presenting cells expressed them, such as dendritic cells, macrophages and other airway epithelial cells, it recognizes molecular patterns associated with microbial pathogens (e.g. bacterial, fungal, and viral structures), and endogenous risk molecules (Vijay 2018). TLR2 is the receptor of fungal β-glucan and gram-positive bacilli 19 peptidoglycan, and TLR4 is the receptor for LPS. TLR3 mediates the downstream signaling pathway through TIR domain-containing adaptor molecule inducing interferon-β (TRIF). After TLR2 and TLR4 bind to their ligands, they can recruit downstream myeloid differentiation factor 88 (MyD88) through TIR-containing adaptor protein (TIRAP), which is crucial for the production of inflammatory factors (Kawai and Akira 2007). NF-κB regulates the expression of many proinflammatory factors, adhesion molecules, and angiogenesis factors. The allergen Der p1 induces NF-κB activation through interference with IκBα function in asthmatic bronchial epithelial cells (Stacey et al. 1997). Yang found that mice deficient in the p50 subunit of NF-κB can not mount eosinophilic airway inflammation compared with wild-type mice. The major defects in the p50(-/-) mice are the lack of production of Th2 cytokine IL-5 and the chemokine eotaxin, which are crucial for proliferation and for differentiation and recruitment of eosinophils into the asthmatic airway, respectively (Yang et al. 1998). Das also found that the p50(-/-) mice can not mount airway eosinophilic inflammation, and this condition is caused by the inability of the p50-/- mice to produce IL-4, IL-5 and IL-13, which play distinct roles in asthma pathogenesis, rather than the defects in TH2 cell recruitment (Das et al. 2001). Hence, we speculate that PM2.5 may activate NF-κB via the TLR2/TLR4/MyD88 signaling pathway to regulate airway inflammation in asthma.