Tetrahedral-Framework Nucleic Acids Carry Small Interfering RNA to Downregulate Toll-Like Receptor 2 Gene Expression for the Treatment of Sepsis

Abstract

Sepsis is caused by the invasion of pathogenic microorganisms, which can lead to excessive expression of toll-like receptors (TLRs) in cells and uncontrollable amplification of the inflammatory response. TLR2, as an essential part of the TLR family, has a significant feature in the identification of innate immune responses. Therefore, blocking the expression and activation of TLR2 can inhibit the synthesis and release of inflammatory factors and avoid the occurrence of excessive inflammatory reactions. Small interfering RNA (siRNA) can selectively target the silencing or downregulation of pathogenic genes and has the advantages of high specificity, a strong effect, and fewer adverse reactions. However, the application of siRNA is limited by its high molecular weight, poor biostability, and difficulty in passive uptake into cells. Tetrahedral-framework nucleic acid (tFNA) is a new kind of three-dimensional nucleic acid nanomaterial, which has the advantages of good biocompatibility, stable structure, and editability. In this study, we used tFNA as carriers to deliver siRNA-targeting downregulation of TLR2 expression for anti-inflammatory therapy. We show that siRNA can specifically reduce lipopolysaccharide (LPS)-induced TLR2 elevation and reduce release of inflammatory factors in LPS-induced experimental sepsis, which provides a new idea for the prevention and treatment of sepsis.

The nano‐windmill exerts superior anti‐inflammatory effects via reducing choline uptake to inhibit macrophage activation

“…First, results of flow cytometry and immunofluorescence images showed that the nano‐windmill was taken up by bone marrow‐derived macrophages (BMDMs) in large quantities in a short time (Figure 2A,B), which revealed its effectively delivered capacities. Second, the RNase H‐responsive sequence was designed to be degraded after entering the cell (Figure 2C), while siR‐slc44a1 gradually dissociated from the nano‐windmill accompanied by the increase of RNase H concentration, identifying the successful separation of the nano‐windmill into tFNA and siR‐slc44a1 (Figure 2D), which is different from the previous tFNA‐based delivery system that tFNA released siRNA with breaking itself and loosing its intact structure after entry into cells, 33,34 such as the nanobox‐siR system 35 or modification of the S2 chain in tFNA 36 . Third, Cy5 was linked to the siR‐slc44a1 for comparing the stability of siR‐slc44a1 in the nano‐windmill system and siR‐slc44a1 alone by observing the degradation of siR‐slc44a1.…”

Functional micro-RNA drugs acting as a fate manipulator in the regulation of osteoblastic death

“…Notably, while this paper focuses on the regulatory role of miRNAs in the RCD pathway, siRNAs, which share a similar structure and function, can also exert silencing effects through the RISC mechanism. 29,32,33 Moreover, siRNAs can be designed to match the base sequences completely, providing stronger specificity and more effective silencing compared to the partial base pairing of miRNAs' seed region ( positions 2-7), and all of the key molecules involved in the RCD pathway can be designed for siRNA-targeting sites. 147 In this review, the role of miRNAs as molecular targeted agents in four modes of regulated cell death in osteoblasts is summarized.…”

“…A TDN-based vertex-multi-sticky end system, 24,31 4. A TDN-based edge-sticky end system, 32 5. A TDN-based RNA-embedded system, 33 6.…”

Functionalized DNA Nanomaterials Targeting Toll‐Like Receptor 4 Prevent Bisphosphonate‐Related Osteonecrosis of the Jaw via Regulating Mitochondrial Homeostasis in Macrophages

“…[18] Additionally, angiogenic peptidecarrying TDNs also benefit BRONJ prevention. [19] Considering previous reports on siRNA-carrying TDNs, [20,21] we further explored the potential of TLR4-siRNA-carrying TDNs (TDN-TLR4-4siR) to decrease the incidence of BRONJ through reversal of macrophageM1/M2 polarization imbalance.…”