Orthodontic space closure following tooth extraction is often hindered by alveolar bone deficiency. This study investigates the therapeutic use of nuclear factor-kappa B (NF-κB) decoy oligodeoxynucleotides loaded with polylactic-co-glycolic acid nanospheres (PLGA-NfDs) to mitigate alveolar bone loss during orthodontic tooth movement (OTM) following the bilateral extraction of maxillary first molars in a controlled experiment involving forty rats of OTM model with ethics approved. The decreased tendency of the OTM distance and inclination angle with increased bone volume and improved trabecular bone structure indicated minimized alveolar bone destruction. Reverse transcription-quantitative polymerase chain reaction and histomorphometric analysis demonstrated the suppression of inflammation and bone resorption by downregulating the expression of tartrate-resistant acid phosphatase, tumor necrosis factor-α, interleukin-1β, cathepsin K, NF-κB p65, and receptor activator of NF-κB ligand while provoking periodontal regeneration by upregulating the expression of alkaline phosphatase, transforming growth factor-β1, osteopontin, and fibroblast growth factor-2. Importantly, relative gene expression over the maxillary second molar compression side in proximity to the alveolus highlighted the pharmacological effect of intra-socket PLGA-NfD administration, as evidenced by elevated osteocalcin expression, indicative of enhanced osteocytogenesis. These findings emphasize that locally administered PLGA-NfD serves as an effective inflammatory suppressor and yields periodontal regenerative responses following tooth extraction.

Liver damage caused by various factors results in fibrosis and inflammation, leading to cirrhosis and cancer. Fibrosis results in the accumulation of extracellular matrix components. The role of STAT proteins in mediating liver inflammation and fibrosis has been well documented; however, approved therapies targeting STAT3 inhibition against liver disease are lacking. This study investigated the anti-fibrotic and anti-inflammatory effects of STAT3 decoy oligodeoxynucleotides (ODN) in hepatocytes and liver fibrosis mouse models. STAT3 decoy ODN were delivered into cells using liposomes and hydrodynamic tail vein injection into 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice in which liver injury was induced. STAT3 target gene expression changes were verified using qPCR and Western blotting. Liver tissue fibrosis and bile duct proliferation were assessed in animal experiments using staining techniques, and macrophage and inflammatory cytokine distribution was verified using immunohistochemistry. STAT3 decoy ODN reduced fibrosis and inflammatory factors in liver cancer cell lines and DDC-induced liver injury mouse model. These results suggest that STAT3 decoy ODN may effectively treat liver fibrosis and must be clinically investigated.

In the present study, we investigated the synergistic effects of targeted methotrexate-selenium nanostructure containing Myc decoy oligodeoxynucleotides along with X-irradiation exposure as a combination therapy on LNCaP prostate cancer cells. Myc decoy ODNs were designed based on the promoter of Bcl-2 gene and analyzed by molecular docking and molecular dynamics assays. ODNs were loaded on the synthesized Se@BSA@Chi-MTX nanostructure. The physicochemical characteristics of nanostructures were determined by FTIR, DLS, UV-vis, TEM, EDX, in vitro release, and hemolysis tests. Subsequently, the cytotoxicity properties of them with and without X-irradiation were investigated by uptake, MTT, cell cycle, apoptosis, and scratch assays on the LNCaP cell line. The results of DLS and TEM showed negative charge (-9 mV) and nanometer size (40 nm) for Se@BSA@Chi-DEC-MTX NPs, respectively. The results of FTIR, UV-vis, and EDX showed the proper interaction of different parts and the correct synthesis of nanoparticles. The results of hemolysis showed the hemocompatibility of this nanoparticle in concentrations less than 6 mg/mL. The ODNs release from the nanostructures showed a pH-dependent manner, and the release rate was 15% higher in acidic pH. The targeted Se@BSA@Chi-labeled ODN-MTX NPs were efficiently taken up by LNCaP cells by targeting the prostate-specific membrane antigen (PSMA). The significant synergistic effects of nanostructure (containing MTX drug) treatment along with X-irradiation showed cell growth inhibition, apoptosis induction (~57%), cell cycle arrest (G2/M phase), and migration inhibition (up to 90%) compared to the control. The results suggested that the Se@BSA@Chi-DEC-MTX NPs can potentially suppress the cell growth of LNCaP cells. This nanostructure system can be a promising approach for targeted drug delivery and chemoradiotherapy in prostate cancer treatment.

Chronic respiratory diseases like asthma and Chronic Obstructive Pulmonary Disease (COPD) have been a burden to society for an extended period. Currently, there are only preventative treatments in the form of mono- or multiple-drug therapy available to patients who need to utilize it daily. Hence, throughout the years there has been a substantial amount of research in understanding what causes inflammation in the context of these diseases. For example, the transcription factor NFκB has a pivotal role in causing chronic inflammation. Subsequent research has been exploring ways to block the activation of NFκB as a potential therapeutic strategy for many inflammatory diseases. One of the possible ways through which this is probable is the utilisation of decoy oligodeoxynucleotides, which are synthetic, short, single-stranded DNA fragments that mimic the consensus binding site of a targeted transcription factor, thereby functionally inactivating it. However, limitations to the implementation of decoy oligodeoxynucleotides include their rapid degradation by intracellular nucleases and the lack of targeted tissue specificity. An advantageous approach to overcome these limitations involves using nanoparticles as a vessel for drug delivery. In this review, all of those key elements will be explored as to how they come together as an application to treat chronic inflammation in respiratory diseases.

Atherosclerosis is a progressive chronic inflammatory condition that is the cause of most cardiovascular and cerebrovascular diseases. The transcription factor nuclear factor‑κB (NF‑κB) regulates a number of genes involved in the inflammatory responses of cells that are critical to atherogenesis, and signal transducer and activator of transcription (STAT)3 is a key transcription factor in immunity and inflammation. Decoy oligodeoxynucleotides (ODNs) bind to sequence‑specific transcription factors and limit gene expression by interfering with transcription in vitro and in vivo. The present study aimed to investigate the beneficial functions of STAT3/NF‑κB decoy ODNs in liposaccharide (LPS)‑induced atherosclerosis in mice. Atherosclerotic injuries of mice were induced via intraperitoneal injection of LPS and the mice were fed an atherogenic diet. Ring‑type STAT3/NF‑κB decoy ODNs were designed and administered via an injection into the tail vein of the mice. To investigate the effect of STAT3/NF‑κB decoy ODNs, electrophoretic mobility shift assay, western blot analysis, histological analysis with hematoxylin and eosin staining, Verhoeff‑Van Gieson and Masson\'s trichrome staining were performed. The results revealed that STAT3/NF‑κB decoy ODNs were able to suppress the development of atherosclerosis by attenuating morphological changes and inflammation in atherosclerotic mice aortae, and by reducing pro‑inflammatory cytokine secretion through inhibition of the STAT3/NF‑κB pathway. In conclusion, the present study provided novel insights into the antiatherogenic molecular mechanism of STAT3/NF‑κB decoy ODNs, which may serve as an additional therapeutic intervention to combat atherosclerosis.

Signal transducer and activator of transcription 3 (STAT3) is a critical regulator for angiogenesis, cell cycle progression, apoptosis, and drug resistance. Resistance toward EGF receptor (EGFR) inhibitors is a significant clinical concern for metastatic colon cancer patients. The present study aimed to evaluate the blocking influences of STAT3 decoy oligodeoxynucleotides (ODNs) on the STAT3 survival signaling pathway in nonresistant and erlotinib-resistant SW480 colon cancer cells. First, STAT3 decoy and scramble ODNs were designed according to STAT3 elements in the promoter region of MYCT1 gene and tested for the interaction of STAT3 protein with designed ODNs via in silico molecular docking study. Then, the efficiency of transfection and subcellular localization of ODNs were assessed using flow cytometry and fluorescence microscopy, respectively. Cell viability, cell cycle, and apoptosis tests, scratch and colony formation assays, and real-time PCR were also used to study the cancerous properties of cells. A considerable decrease in proliferation of colon cancer cells was observed with blockade of STAT3 signaling due to cell cycle arrest and induced apoptosis via downregulation of cyclin D1 and Bcl-XL, respectively. Furthermore, upon transfecting STAT3 decoy ODNs, colony formation potential and migration activity in both SW480 colon cancer cell lines were decreased compared to the control groups. From this study, it could be concluded that STAT3 is critical for cell growth inhibition and metastatic properties reduction of resistant SW480 colon cancer cells; therefore, STAT3 decoy ODNs could be considered as potential therapeutics along with current remedies for treating drug-resistant colon cancer.

Recently, advances in the synthesis and development of multifunctional nanoparticle platforms have opened up great opportunities and advantages for specifically targeted delivery of genes of interest. BSA-coated niosome structures (NISM@B) can potentially improve the efficiency in vitro delivery of nucleic acid molecules and the transfection of genes. Few studies have reported the combined use of niosomes with nucleic acid as therapeutic agents or decoy oligodeoxynucleotides (ODNs). Herein, we synthesized NISM@B to encapsulate NANOG decoy ODN (NISM@B-DEC), after which the physicochemical characteristics and in vitro and in vivo properties of NISM@B-DEC were investigated. Our results regarding physicochemical characteristics revealed that the stable niosome nanocarrier system was successfully synthesized with a regular spherical shape and narrow size distribution with proper zeta-potential values and had an appropriate biocompatibility. The ODN release from the niosome nanocarrier system exhibited controlled and pH-dependent behavior as the best models to explain the ODN release profile. NISM@B-DEC was efficiently taken up by human glioblastoma cells (U87) and significantly inhibited cell growth. Finally, blockage of the NANOG pathway by NISM@B-DEC resulted in G1 cell cycle arrest, apoptosis, and cell death. In addition, NISM@B-DEC caused a significant decrease in tumor formation and improved wound-healing efficiency of the U87 cells. These findings confirm that NISM@B-DEC could potentially suppress the metastatic ability of these cells. It can be concluded that the presented nanocarrier system can be a promising approach for targeted gene delivery in cancer therapy.

Despite recent advances, non-Hodgkin\'s B cell lymphoma patients often relapse or remain refractory to therapy. Therapeutic resistance is often associated with survival signaling via nuclear factor κB (NF-κB) transcription factor, an attractive but undruggable molecular target. In this study, we describe a bipartite inhibitor comprising a NF-κB-specific decoy DNA tethered to a CpG oligodeoxynucleotide (ODN) targeting Toll-like receptor-9-expressing B cell lymphoma cells. The Bc-NFκBdODN showed efficient uptake by human diffuse large B cell (U2932, OCI-Ly3), Burkitt (RaJi), and mantle cell (Jeko1) lymphomas, respectively. We confirmed that Bc-NFκBdODN inhibited NF-κB nuclear translocation and DNA binding, resulting in CCND2 and MYC downregulation. Bc-NFκBdODN enhanced radiosensitivity of lymphoma cells in vitro. In xenotransplanted human lymphoma, local injections of Bc-NFκBdODN reduced NF-κB activity in whole tumors. When combined with a local 3-Gy dose of radiation, Bc-NFκBdODN effectively arrested OCI-Ly3 lymphoma progression. In immunocompetent mice, intratumoral injections of Bc-NFκBdODN suppressed growth of directly treated and distant A20 lymphomas, as a result of systemic CD8 T cell-dependent immune responses. Finally, systemic administration of Bc-NFκBdODN to mice bearing disseminated A20 lymphoma induced complete regression and extended survival of most of the treated mice. Our results underscore clinical relevance of this strategy as monotherapy and in support of radiation therapy to benefit patients with resistant or relapsed B cell lymphoma.

Rheumatoid arthritis (RA) is an autoimmune disease that is currently incurable. Clinical practice has shown significant benefits of combined therapies for RA treatment. This study aims to develop and demonstrate an efficient triple therapy for RA in vitro and in vivo. Three anti-inflammatory agents, NF-κB decoy oligodeoxynucleotides (ODNs), gold nanorods (GNRs), and dexamethasone (DEX), were encapsulated into folate (FA) modified liposomes (FA-lip(DEX + GNRs/ODNs)). The FA-lip(DEX + GNRs/ODNs) showed favorable physicochemical properties and efficient intracellular uptake by inflamed macrophages. Combined with laser irradiation, FA-lip(DEX + GNRs/ODNs) greatly reduced the secretion of proinflammatory proteins and oxidative factors in vitro. In adjuvant-induced arthritis (AIA) mice, FA-lip(DEX + GNRs/ODNs) achieved prolonged and enhanced accumulation at inflamed paws. FA-lip(DEX + GNRs/ODNs) + laser treatment reduced clinical arthritis scores and serum cytokine levels and protected cartilage. In summary, the triple therapy demonstrated significantly enhanced anti-inflammatory efficacy and is a promising strategy to treat RA via combined anti-inflammatory mechanisms.

Rheumatoid arthritis (RA) is an autoimmune disease featured with chronic joint inflammation. Suppression of inflammation is critical to RA treatment and joint protection. In this study, DNA nanodrugs are prepared via the conjugation of NF-κB decoy oligodeoxynucleotides (dODNs) and VCAM-1 targeted peptides (P) onto self-assembled DNA tetrahedrons (TDs). Physicochemical properties of DNA nanodrugs are characterized using atomic force microscopy (AFM), gel electrophoresis and Fourier Transform Infrared Spectrometer (FTIR). Cytotoxicity, cellular uptake and anti-inflammatory efficacy of DNA nanodrugs are evaluated in vitro. Clinical arthritis index, inflammatory proteins in serum and joint pathophysiology are also investigated in vivo. TD-P-dODN possesses one dODN and one P and exhibits faster and higher cellular uptake by inflammatory cells compared with free dODNs. TD-P-dODN also significantly reduce inflammatory proteins in cells and adjuvant induced arthritis (AIA) mice. Reduced clinical arthritis index and improved joint rehabilitation are also achieved by TD-P-dODN treatment. This study demonstrates that an engineered DNA nanodrug (TD-P-dODN) enhances the efficacy of nucleic acid drugs and represents a promising strategy for RA treatment.